Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types
© Ling et al; licensee BioMed Central Ltd. 2010
Received: 6 July 2009
Accepted: 22 January 2010
Published: 22 January 2010
Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. Methods: In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology.
We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time.
Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.
Although bortezomib (PS-341) was largely applied to treatment of hematopoietic malignancy such as myeloma, growing basic studies and clinical trials reveal that bortezomib can be used to treat many types of solid tumors alone and in combination with other chemotherapeutic drugs. This includes colon-gastric cancer [1–3], breast cancer [4–9], prostate cancer [10–14] and lung cancer [15–18] as well as others. Therefore, use of solid tumor-derived cancer cell lines to study the mechanism of bortezomib drug resistance is important for effective application of bortezomib in treatment of patients with solid tumors in the clinic.
Survivin, a unique member of the Inhibitor of Apoptosis (IAP) Protein Family, is cell cycle-regulated [19, 20] and its expression in cancer has been associated with cancer progression, drug resistance, and shortened patient survival [21, 22]. Given that survivin is highly expressed in malignant cells but is undetectable in most normal adult tissues, it is considered as a potentially important therapeutic target . Survivin antagonizes apoptosis and is involved in the mitotic spindle assembly checkpoint [24, 25]. Thus, inhibition of survivin expression or function induces both apoptosis and cell division defect. Many protein factors and signaling transduction pathways can modulate the expression of survivin . For example, it has been reported that p53 transcriptionally downregulates the expression of survivin in various cancer cells with wild type p53 [27–29], and the inhibition of survivin by p53 can be reversed by growth-stimulatory factors such as estrogen receptor-α .
While survivin is a known universal drug resistant factor, the role and expression for survivin in bortezomib-induced cancer cell growth inhibition and apoptosis induction remains unclear. Some of the previous reports noted that treatment of cancer cells with bortezomib is associated with enhanced apoptosis and reduced expression of survivin [31, 32], while other investigators reported that bortezomib-induced apoptosis is accompanied with an induction of survivin expression in human NSCLC cells . Recently, it has been also reported that the role for survivin in bortezomib-induced apoptosis is cell type-dependent . In this study, we demonstrated that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell type. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib either downregulates or shows no significant effect on survivin, which is dependent on cell line, bortezomib concentration and duration of exposure. These findings, for the first time, unified the current different observations about the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance, and warranted further mechanistic studies and application of these findings in cancer therapeutics.
Cell culture and reagents
Colon cancer cell lines (HCT116p53+/+, HCT116p53-/-), lung cancer cell lines (EKVX and A549), prostate cancer cells (PC-3 and LNCaP) and multiple myeloma cell lines (KMS11 and RPMI8226) were maintained in RPMI 1640 medium. Breast cancer cells (MDA-MB-231 and MCF-7) were cultured in DMEM medium. All cell cultural mediums were supplied with 10% fetal bovine serum (FBS, Atlanta Biologicals, Lawrenceville, GA) and penicillin (100 units/ml)/streptomycin (0.1 μg/ml) (Invitrogen, Grand Island, NY). Cells were routinely subcultured twice a week and maintained in a humidified incubator with 5% CO2 at 37°C. Polyclonal anti-actin antibody and goat peroxidase-conjugated anti-rabbit IgG antibody were purchased from Sigma (St. Louis, MO). Survivin antibody (FL-142) was purchased from Santa Cruz (Santa Cruz, CA), MTT (tetrazolium salt, 3- [4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide) and leupeptin were purchased from Usb (Cleveland, OH).
Cell treatment and siRNA/shRNA transfection/infection
Cells grown in medium containing 10% serum were treated with and without bortezomib in various concentrations (see text and results) for 24 - 72 hours were harvested and followed by various analyses. siRNA transfection  and shRNA infection  were performed as previously described
MTT cell viability assay
Effect of bortezomib on cell growth was determined by MTT assay. MTT was used as a colorimetric substrate for measuring cell viability. Non-viable cells, with altered cellular redox activity, are unable to reduce the MTT dye. After 72 hours with or without bortezomib treatment, MTT was added (to a final concentration of 0.5 mg/ml). Cells in 96-well plates were incubated in a 5% CO2 incubator at 37°C for 4 hours, and then lysed thoroughly with lysis buffer (20% SDS, 50% N, N-dimethylformamide, pH 4.7, 100 μl/well). The absorbance in the relevant wells was measured at 570 nm using an Ultra Microplate Reader (Bio-Tek Instruments).
Flow cytometry analysis
Cells at sub-confluence (~30%) were treated with bortezomib at 0, 5, 10 and 50 nM for 48 hours and then harvested by trypsinization and washed with PBS. Cells (~1 × 106) were resuspended in 5 ml 70% ethanol. After the initial fixation, cells were suspended in 0.5 ml PBS containing 25 μg/ml propidium iodide (PI), 0.2% Triton X-100 and 40 μg/ml RNase A and incubated for at least 30 minutes at 4°C. Cells were then analyzed for DNA content profile by flow cytometry (FACScan, Becton Dickinson, San Jose, CA) from 10,000 events per sample. Data from flow cytometry were analyzed using WinList software (Verity Software House Inc., Topsham, ME) and presented as DNA content profiles (X axle) over cell numbers (y axle). Triplicate assays were performed.
Western blot analysis
Cells with and without bortezomib treatment were washed with phosphate-buffered saline (PBS) and lysed on ice for 30 minutes in PBS containing 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS), 10 μg/ml phenylmethyl sulfonyl fluoride, and 20 μM leupeptin. Cell lysates were then centrifuged at 15,000 g for 20 minutes at 4°C. Fifty μg total proteins from each sample were heated at 95°C for 5 minutes after mixing with equal volume of 2 × SDS loading buffer. Samples were separated on 12 - 15% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) gels and electrotransferred to Pure Nitrocellulose Membranes (Bio-Rad, Hercules, CA). The membrane was then blocked in 5% skim milk in TBS-T buffer (20 mM Tris/HCl (pH 7.5), 0.137 M NaCl, and 0.05% Tween 20) at room temperature for 2-3 hours; followed by incubation of the membrane with primary antibodies (against survivin or actin) in TBS-T containing 5% BSA overnight at 4°C in the range of dilutions from 1:1000 to 1:4000. After washing with TBS-T, the membrane was incubated in TBS-T buffer containing 5% skim milk containing the corresponding secondary antibody (1:5000) for 45-60 minutes at room temperature with shaking. Protein of interest was detected using ECL (Perkin Elmer, Waltham, MA) and visualized by autoradiography with various times (5-60 seconds) of exposure. Actin was detected as the internal control for normalization of total protein loading in each lane.
Cell death detection ELISA assay
This assay is based on cell DNA fragmentation and the cell death/DNA fragmentation was detected using the Cell Death Detection ELISAPlus assay kit (Roche) as described previously . Briefly, transfected HCT116p53-/- cells were seeded in triplicates in 96-well plates and treated with and without bortezomib for 48 hours. After removing medium, cells were then lysed and 20 μl of lysate supernatant from each well were dispensed into streptavidin-coated well-removable 96-well plates followed by addition of 80 μl of immuno-reagents. After a 2-hour incubation at room temperature, unbound components were removed by washing with 1× incubation buffer for 3 times, followed by adding 100 μl of HRP substrate to each well, and the plate was placed on a shaker at 250 rpm for color development. Measurements were made at 405 nm against an ABTS solution as a blank control using a microplate reader. The absorbance value at 405 nm represents the quantities of DNA fragments/apoptosis induced by the treatment.
A t-test was performed for a pair-wise comparison of each experimental pair group with the control assuming equal variance. The significance (p-value marked with an asterisk "*") was set at equal to or less than 0.05.
Bortezomib-induced growth inhibition in HCT116 colon cancer cells is dependent on p53 statuses
HCT116p53-/- colon cancer cells are much more resistant to bortezomib-mediated cell death in comparison with wild type HCT116 cells
Survivin expression is much higher in HCT116p53-/- cells than in HCT116p53+/+ cells
Bortezomib induces survivin expression in HCT116p53-/- cells but shows no significant effect on survivin expression in HCT116p53+/+ cells
Silencing of survivin expression in HCT116p53-/- cells by survivin mRNA-specific siRNA sensitizes bortezomib-induced growth inhibition
Cancer cell sensitivity to bortezomib treatment is dependent on p53 status but not cancer cell types
Bortezomib is the first in class, proteasome inhibitor that has demonstrated significant anticancer activity in patients with lymphoid malignancies especially multiple myeloma [38, 39]. However, growing studies indicated the potential effectiveness of bortezomib in treatment of patients with solid tumor including colon-gastric cancer [1–3], breast cancer [4–9], prostate cancer [10–14] and lung cancer [15–18]. However, despite its impressive single agent clinical activity in patients with either hematopoietic or solid malignancy, most patients either fail to respond or develop resistance to bortezomib treatment. Therefore, resistance to bortezomib is a challenging problem in the clinic. Identifying mechanism of bortezomib resistance not only can help identify novel therapeutic targets but will also contribute to better utilization of this important therapeutic agent.
In the present study, we focus on the role of survivin and p53 in bortezomib effectiveness as well as their functional relationship in solid tumor cell lines. We found that cancer cells with wild type p53 express much less survivin in comparison with cancer cells with either mutant or null p53. Moreover, bortezomib significantly increased survivin expression in the HCT116 colon or other cancer cell lines with p53 null, while it only showed a minimal effect on survivin expression in HCT116 and other cancer cells with wild type p53. Consistent with these findings, while bortezomib effectively inhibited cell growth and induced cell death in cancer cells with wild type p53, bortezomib showed ineffectiveness to inhibit cell growth and induce cell death for the cancer cells with abnormal p53 (null or mutated). We recognized that our experiment in Fig. 7 will be more convincing, if pairs of cancer cell lines as we have for the HCT116 line (HCT116p53+/+ vs. HCT116p53-/-) could be available to us for these experiment. Nevertheless, the role of survivin in bortezomib resistance was directly demonstrated in the study by silencing of survivin in several cancer cell lines with mutant p53 using survivin mRNA-specific siRNA/shRNA technology previously set up in our laboratory [35, 36]. Finally, our investigations in three different pair of cancer cell lines (originating from breast, lung and prostate) with different p53 status demonstrated that the p53 status-associated survivin expression is an essential parameter to predict bortezomib resistance irrespective of the origin of the cancer cell. Cancer cells having a wild type p53 were sensitive while those with abnormal p53 (mutated or null) were resistant to bortezomib treatment. Consistent with these findings, previous studies found that wild type p53 transcriptionally inhibits survivin expression in various cancer cell types [27–29] and bortezomib can stabilize wild type p53 in prostate cancer cells . Here, we would like to point out that the bortezomib concentration used affects the results, suggesting the dose used in the clinic should be carefully considered. When high dose may kill cancer cells better in a short term, high dose will increase the possibility to generate bortezomib resistance, suggesting that in addition to p53 status-associated survivin expression, other factors, such as other protein members in the IAP and Bcl-2 families may also play important roles in bortezomib resistance. Nevertheless, we have confirmed a role for survivin in bortezomib resistance by direct silencing of survivin expression using survivin-specific siRNA/shRNA. This finding is significant because our recent studies indicated that survivin may be a superior cancer stem cell marker and possibly plays critical role in cancer stem cell expansion . In this regard, cancer cells appear to have a higher percentage of subpopulation cells that are tumorigenic (cancer initiating/cancer stem cells) in xenograft mouse models .
Therefore, consideration of both survivin expression and p53 status as interconnecting biomarkers and targets in cancer cells may not only be useful for predicting the outcome of bortezomib treatment, but may also provide pivotal criteria for rational drug combination. For example, bortezomib likely induces survivin expression in cancer cells with mutated or null p53 (this study), and it is known that paclitaxel rapidly induces survivin expression . Thus, combination of bortezomib and paclitaxel likely obtained no good results in many cancer types with such as the mutated p53 background. Accordingly, a recent Phase II study in patients with metastatic esophageal, gastric, and gastroesophageal cancer showed poor results in the drug combination . However, it is also possible that the poor results derived from such a drug combination involve other mechanisms of drug resistance in these tumors that are notoriously difficult to treat with chemotherapy.
An important question that needs be answered for better application of the findings is the mechanism underlying bortezomib-mediated induction of survivin expression in mutated or null p53 cancer cells, while it showed downregulation of or minimal effect on survivin expression in wild type p53 cancer cells. Although answering this critical question will need further research efforts, based on the current available information, the potential p53 and NF-κB functional crosstalk could provide a plausible explanation, although need to be further confirmed. As reviewed before, the survivin gene is a potential downstream target for p53 and NF-κB transcriptional regulation . Alternatively, the previous finding that bortezomib stabilizes active form of p53 in human LNCaP-Pro5 prostate cancer cells may provide another explanation . Nevertheless, while survivin expression is inhibited by wild type p53 [27–29], survivin and NF-κB appear to be co-expressed in cancer such as in peripheral T-cell lymphoma , and inhibition of NF-κB activity using NF-κB-specific inhibitors decreased survivin expression . Consistent with these observations, bortezomib resistance requires NF-κB activity in mantle cell lymphoma . Therefore, the potential connection of these factors provide an interesting underlying mechanism, which is likely similar to the mechanism we recently discovered for the p53 and ERα on the survivin gene control in the breast cancer .
Finally, the p53 status in RPMI-8226 and Kms11 is not fully consistent in literature. Our literature search indicates that RPMI-8226 has mutant p53 , while Kms11 has wild type p53. However, some publication indicated that Kms11 is p53 null. This is likely due to the hypermethylation of the p53 gene to make p53 expression extremely low . Consistently, our results (Li and Chanan-Khan, unpublished observation) indicated that the expression of p53 in Kms11 was barely detected. Consistent with this, we found that the expression of survivin in Kms11 is comparable with its level in RPMI-8226 (Fig. 3C).
In conclusion, based on the finding in this study, survivin appears to play a role in bortezomib resistance. The p53 status-associated survivin expression is an important parameter for predicting bortezomib sensitivity, which is largely independent of cancer cell types. Therefore, the finding in this paper should be useful for not only prediction of bortezomib sensitivity, but may also be useful as an essential criterion for bortezomib combination with other anticancer compounds for treatment of cancer patients.
Diane Calinski was a student in the Roswell Park Summer College Student Program at the time for this work.
PS-341 OR velcade®
inhibitor of apoptosis
tetrazolium salt, 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide
non-small cell lung cancer
small interference RNA.
This work was supported in part by NIH R01 Grants (CA109481, CA133241), a research grant (BCTR63806) from the Susan G. Komen for the Cure Foundation and a research grant from Charlotte Geyer Foundation to FL, and by the NCI Cancer Center Support Grant to the Roswell Park Cancer Institute (CA016056). ACK is a Scholar of the Leukemia and lymphoma Society.
- Fujita T, Doihara H, Washio K, Ino H, Murakami M, Naito M, Shimizu N: Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells. Anticancer Drugs. 2007, 18: 677-686. 10.1097/CAD.0b013e32808bf9d8.View ArticleGoogle Scholar
- Mackay H, Hedley D, Major P, Townsley C, Mackenzie M, Vincent M, Degendorfer P, Tsao MS, Nicklee T, Birle D, et al: A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res. 2005, 11: 5526-5533. 10.1158/1078-0432.CCR-05-0081.View ArticleGoogle Scholar
- Kozuch PS, Rocha-Lima CM, Dragovich T, Hochster H, O'Neil BH, Atiq OT, Pipas JM, Ryan DP, Lenz HJ: Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase II study. J Clin Oncol. 2008, 26: 2320-2326. 10.1200/JCO.2007.14.0152.View ArticleGoogle Scholar
- Cardoso F, Durbecq V, Laes JF, Badran B, Lagneaux L, Bex F, Desmedt C, Willard-Gallo K, Ross JS, Burny A, et al: Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner. Mol Cancer Ther. 2006, 5: 3042-3051. 10.1158/1535-7163.MCT-06-0104.View ArticleGoogle Scholar
- Codony-Servat J, Tapia MA, Bosch M, Oliva C, Domingo-Domenech J, Mellado B, Rolfe M, Ross JS, Gascon P, Rovira A, Albanell J: Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells. Mol Cancer Ther. 2006, 5: 665-675. 10.1158/1535-7163.MCT-05-0147.View ArticleGoogle Scholar
- Yang CH, Gonzalez-Angulo AM, Reuben JM, Booser DJ, Pusztai L, Krishnamurthy S, Esseltine D, Stec J, Broglio KR, Islam R, et al: Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol. 2006, 17: 813-817. 10.1093/annonc/mdj131.View ArticleGoogle Scholar
- Engel RH, Brown JA, Von Roenn JH, O'Regan RM, Bergan R, Badve S, Rademaker A, Gradishar WJ: A phase II study of single agent bortezomib in patients with metastatic breast cancer: a single institution experience. Cancer Invest. 2007, 25: 733-737. 10.1080/07357900701506573.View ArticleGoogle Scholar
- Awada A, Albanell J, Canney PA, Dirix LY, Gil T, Cardoso F, Gascon P, Piccart MJ, Baselga J: Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study. Br J Cancer. 2008, 98: 1500-1507. 10.1038/sj.bjc.6604347.View ArticleGoogle Scholar
- Schmid P, Kuhnhardt D, Kiewe P, Lehenbauer-Dehm S, Schippinger W, Greil R, Lange W, Preiss J, Niederle N, Brossart P, et al: A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines. Ann Oncol. 2008, 19: 871-876. 10.1093/annonc/mdm569.View ArticleGoogle Scholar
- Papandreou CN, Logothetis CJ: Bortezomib as a potential treatment for prostate cancer. Cancer Res. 2004, 64: 5036-5043. 10.1158/0008-5472.CAN-03-2707.View ArticleGoogle Scholar
- Price N, Dreicer R: Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Prostate Cancer. 2004, 3: 141-143.View ArticleGoogle Scholar
- Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, Pien CS, Millikan RE, Tu SM, Pagliaro L, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004, 22: 2108-2121. 10.1200/JCO.2004.02.106.View ArticleGoogle Scholar
- Morris MJ, Kelly WK, Slovin S, Ryan C, Eicher C, Heller G, Scher HI: A phase II trial of bortezomib and prednisone for castration resistant metastatic prostate cancer. J Urol. 2007, 178: 2378-2383. 10.1016/j.juro.2007.08.015.View ArticleGoogle Scholar
- Dreicer R, Petrylak D, Agus D, Webb I, Roth B: Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Cancer Res. 2007, 13: 1208-1215. 10.1158/1078-0432.CCR-06-2046.View ArticleGoogle Scholar
- Reddy KG: Activity of bortezomib in advanced non-small-cell lung cancer. Clin Lung Cancer. 2004, 6: 141-142.View ArticleGoogle Scholar
- Fanucchi MP, Fossella FV, Belt R, Natale R, Fidias P, Carbone DP, Govindan R, Raez LE, Robert F, Ribeiro M, et al: Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2006, 24: 5025-5033. 10.1200/JCO.2006.06.1853.View ArticleGoogle Scholar
- Lilenbaum R, Wang X, Gu L, Kirshner J, Lerro K, Vokes E: Randomized phase II trial of docetaxel plus cetuximab or docetaxel plus bortezomib in patients with advanced non-small-cell lung cancer and a performance status of 2: CALGB 30402. J Clin Oncol. 2009, 27: 4487-4491. 10.1200/JCO.2009.22.7066.View ArticleGoogle Scholar
- Li T, Ho L, Piperdi B, Elrafei T, Camacho FJ, Rigas JR, Perez-Soler R, Gucalp R: Phase II study of the proteasome inhibitor bortezomib (PS-341, Velcade((R))) in chemotherapy-naive patients with advanced stage non-small cell lung cancer (NSCLC). Lung Cancer. 2009Google Scholar
- Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998, 396: 580-584. 10.1038/25141.View ArticleGoogle Scholar
- Altieri DC: Survivin in apoptosis control and cell cycle regulation in cancer. Prog Cell Cycle Res. 2003, 5: 447-452.Google Scholar
- Li F: Survivin Study: What is the next wave?. J Cell Physiol. 2003, 197: 8-29. 10.1002/jcp.10327.View ArticleGoogle Scholar
- Li F, Ling X: Survivin Study: An update of "What is the next wave?". J Cell Physiol. 2006, 208: 476-486. 10.1002/jcp.20634.View ArticleGoogle Scholar
- Pennati M, Folini M, Zaffaroni N: Targeting survivin in cancer therapy. Expert Opin Ther Targets. 2008, 12: 463-476. 10.1517/14728184.108.40.2063.View ArticleGoogle Scholar
- Altieri DC: The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol. 2006, 18: 609-615. 10.1016/j.ceb.2006.08.015.View ArticleGoogle Scholar
- Wheatley SP, McNeish IA: Survivin: a protein with dual roles in mitosis and apoptosis. Int Rev Cytol. 2005, 247: 35-88. 10.1016/S0074-7696(05)47002-3.View ArticleGoogle Scholar
- Zhang M, Yang J, Li F: Transcriptional and post-transcriptional controls of survivin in cancer cells: novel approaches for cancer treatment. J Exp Clin Cancer Res. 2006, 25: 391-402.Google Scholar
- Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, Wen SF, Wang L, Kirschmeier P, Bishop WR, et al: Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene. 2002, 21: 2613-2622. 10.1038/sj.onc.1205353.View ArticleGoogle Scholar
- Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M: Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 2002, 277: 3247-3257. 10.1074/jbc.M106643200.View ArticleGoogle Scholar
- Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW: DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells. J Pharmacol Exp Ther. 2002, 303: 124-131. 10.1124/jpet.102.037192.View ArticleGoogle Scholar
- Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM: Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res. 2007, 67: 7746-7755. 10.1158/0008-5472.CAN-06-3724.View ArticleGoogle Scholar
- Vaziri SA, Hill J, Chikamori K, Grabowski DR, Takigawa N, Chawla-Sarkar M, Rybicki LR, Gudkov AV, Mekhail T, Bukowski RM, et al: Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3sigma and survivin. Mol Cancer Ther. 2005, 4: 1880-1890. 10.1158/1535-7163.MCT-05-0222.View ArticleGoogle Scholar
- Gordon GJ, Mani M, Maulik G, Mukhopadhyay L, Yeap BY, Kindler HL, Salgia R, Sugarbaker DJ, Bueno R: Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma. Cancer Chemother Pharmacol. 2007, 61 (4): 549-58. 10.1007/s00280-007-0500-1.View ArticleGoogle Scholar
- Liu X, Yue P, Chen S, Hu L, Lonial S, Khuri FR, Sun SY: The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res. 2007, 67: 4981-4988. 10.1158/0008-5472.CAN-06-4274.View ArticleGoogle Scholar
- Jung CS, Zhou Z, Khuri FR, Sun SY: Assessment of Apoptosis-Inducing Effects of Docetaxel Combined with the Proteasome Inhibitor PS-341 in Human Lung Cancer Cells. Cancer Biol Ther. 2007, 6 (5): 749-54.View ArticleGoogle Scholar
- Ling X, Li F: Silencing of antiapoptotic survivin gene by multiple approaches of RNA interference technology. BioTechniques. 2004, 36: 450-454. 456-460Google Scholar
- Ling X, Cheng Q, Black JD, Li F: Forced Expression of Survivin-2B Abrogates Mitotic Cells and Induces Mitochondria-dependent Apoptosis by Blockade of Tubulin Polymerization and Modulation of Bcl-2, Bax, and Survivin. J Biol Chem. 2007, 282: 27204-27214. 10.1074/jbc.M705161200.View ArticleGoogle Scholar
- Ling X, He X, Apontes P, Cao F, Azrak RG, Li F: Enhancing effectiveness of the MDR-sensitive compound T138067 using advanced treatment with negative modulators of the drug-resistant protein survivin. Am J Transl Res. 2009, 1: 393-405.Google Scholar
- Laubach JP, Mitsiades CS, Roccaro AM, Ghobrial IM, Anderson KC, Richardson PG: Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenstroms Macroglobulinemia. Leuk Lymphoma. 2009, 50: 694-702. 10.1080/10428190902866732.View ArticleGoogle Scholar
- Curran MP, McKeage K: Bortezomib: a review of its use in patients with multiple myeloma. Drugs. 2009, 69: 859-888. 10.2165/00003495-200969070-00006.View ArticleGoogle Scholar
- Williams SA, McConkey DJ: The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells. Cancer Res. 2003, 63: 7338-7344.Google Scholar
- Li F, Cheng Q, Ling X, Stablewski A, Tang L, Foster BA, Johnson CS, Rustum YM, Porter CW: Generation of a novel transgenic mouse model for bioluminescent monitoring of survivin gene activity in vivo at various pathophysiological processes: Survivin expression overlaps with stem cell markers. Am J Pathol. 2010.Google Scholar
- Li F: Every single cell clones from cancer cell lines growing tumors in vivo may not invalidate the cancer stem cell concept. Mol Cells. 2009, 27: 491-492. 10.1007/s10059-009-0056-5.View ArticleGoogle Scholar
- Ling X, Bernacki RJ, Brattain MG, Li F: Induction of survivin expression by taxol (paclitaxel) is an early event which is independent on taxol-mediated G2/M arrest. J Biol Chem. 2004, 279: 15196-15203. 10.1074/jbc.M310947200.View ArticleGoogle Scholar
- Jatoi A, Dakhil SR, Foster NR, Ma C, Rowland KM, Moore DF, Jaslowski AJ, Thomas SP, Hauge MD, Flynn PJ, et al: Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esophageal, gastric, and gastroesophageal cancer: phase II results from the North Central Cancer Treatment Group (N044B). J Thorac Oncol. 2008, 3: 516-520. 10.1097/JTO.0b013e31816de276.View ArticleGoogle Scholar
- Chang H, Gao Y, Zhang JY, Shi F, Chen YZ: [Expression of survivin and NF-kappaB in peripheral T-cell lymphoma and its significance.]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008, 16: 1079-1081.Google Scholar
- Sato A, Oya M, Ito K, Mizuno R, Horiguchi Y, Umezawa K, Hayakawa M, Murai M: Survivin associates with cell proliferation in renal cancer cells: regulation of survivin expression by insulin-like growth factor-1, interferon-gamma and a novel NF-kappaB inhibitor. Int J Oncol. 2006, 28: 841-846.Google Scholar
- Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S: Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer. 2008, 7: 40-10.1186/1476-4598-7-40.View ArticleGoogle Scholar
- Liu Q, Hilsenbeck S, Gazitt Y: Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood. 2003, 101: 4078-4087. 10.1182/blood-2002-10-3231.View ArticleGoogle Scholar
- Ooi MG, Hayden PJ, Kotoula V, McMillin DW, Charalambous E, Daskalaki E, Raje NS, Munshi NC, Chauhan D, Hideshima T, et al: Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clin Cancer Res. 2009, 15: 7153-7160. 10.1158/1078-0432.CCR-09-1071.View ArticleGoogle Scholar
- Hurt EM, Thomas SB, Peng B, Farrar WL: Reversal of p53 epigenetic silencing in multiple myeloma permits apoptosis by a p53 activator. Cancer Biol Ther. 2006, 5: 1154-1160. 10.1158/1535-7163.MCT-05-0446.View ArticleGoogle Scholar
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