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Current implications of cyclophilins in human cancers


Cyclophilins (Cyps), the intracellular receptor for immunosuppressant cyclosporine A (CsA), play important cellular roles through activities of peptidyl-prolyl cis-trans isomerase (PPIase) and chaperones. Cyps are structurally conserved and found in both prokaryotic and eukaryotic organisms, including humans which contain 16 Cyp isoforms. Although human Cyps were identified about 25 years ago, their physiological and pathological roles have only been the focus of attention recently because of their possible involvement in diseases and ailments such as HIV infection, hepatitis B and C viral infection, atherosclerosis, ER stress-related diseases and neurodegenerative diseases, etc. There are reports for upregulated Cyps in many human cancers and there are also strong correlations found between Cyps overexpression and malignant transformation. This review discusses the important and diverse roles of Cyps overexpression in human cancers. Understanding biological functions of Cyps will eventually lead to improved strategies for cancer treatment and prevention.


Cyclophilins (Cyps) were initially identified as biological receptors for the immunosuppressive drug cyclosporine A (CsA) approximately 25 years ago. Later, they were shown to have peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity which catalyzes cis-trans isomerization of peptide bonds preceding proline [16]. Cyps also possess chaperone activities. These two functions allow Cyps to be involved in proper folding of proteins in combination with other proteins. Although CsA is an effective inhibitor of Cyps, immunosuppressive activity of CsA is not the result of inhibition of the Cyps' activities. Rather, the Cyp-CsA complex accidentally inhibits calcineurin activity and thereby suppresses T-cell proliferation by interfering with downstream signal transduction [7].

Cyps are highly conserved from E. coli to humans throughout evolution. A total of 16 Cyp isoforms have been found in humans [8], but 7 major human Cyp isoforms, namely hCypA, hCypB, hCypC, hCypD, hCypE, hCyp40, and hCypNK [9], have been well characterized. They play diverse roles by localizing through unique domains for particular cellular compartments including the cytosol, endoplasmic reticulum (ER), mitochondria and nucleus. The clinical importance of Cyps has been implicated in diverse pathological conditions including HIV [10], hepatitis B and C viral infection, atherosclerosis [11, 12], ER stress-related diseases such as diabetes, and neurodegenerative diseases. Cyps are also involved in normal cellular functions of muscle differentiation, detoxification of reactive oxygen species (ROS) [13], and immune response [14]. Their novel and unfamiliar nuclease activity similar to apoptotic endonucleases suggests a potential role in apoptotic DNA degradation. Overall roles of Cyps may encompass far more than already defined functions such as protein folding.

CypA overexpression in diverse types of cancer has been recently reported by many research groups. Subsequently, overexpression of other Cyps has also been repeatedly observed in various cancers. Although Cyps expression levels and patterns in many cancer types have been considerably well documented, the precise roles of Cyps in cancer are hardly defined. Here, we will discuss the implications of Cyps in cancer biology and particularly give emphasis on CypA that has been studied most extensively in diverse human cancers. Better understanding of Cyps' function in cancers may divulge their potential applications in cancer prevention, diagnosis, and treatment.

Regulation of Cyclophilin A gene expression in human cancers

After the initial finding of upregulation of CypA in hepatocellular carcinoma [15, 16], CypA has been reported to be overexpressed in small cell lung cancer [1720], pancreatic cancer [2125], breast cancer [26, 27], colorectal cancer [2830], squamous cell carcinoma [31, 32], melanoma [33], and glioblastoma multiforme [34]. In addition to CypA's automatic malregulation in diverse cancers, CypA can be influenced in its expression by chemotherapeutic agents. Independent research groups demonstrated that treatment with chemotherapeutic agents, 5-aza-2-deoxycytidine (DAC), celecoxib, and 5-fluorouracil (5-FU), lowers CypA expression [[21, 29] and [30]]. On the contrary, our group found that cisplatin causes CypA overexpression and induces resistance to diverse chemotherapeutic agents including cisplatin (unpublished data). Upregulation of CypA in cancer is not so unusual; yet the exact mechanisms of transcriptional alteration of CypA in cancer are still elusive.

Initially, CypA gene together with those of glyceraldehyde 3-phosphate dehydrogenase, rRNA and beta-actin was considered one of the constitutively expressed house- keeping genes which do not respond to external stimuli. Considering the chaperone activity of CypA protein, it is not surprising to find up-regulation of CypA gene in response to stresses that can cause protein damage or denaturation [35]. Since molecular regulatory mechanisms of CypA expression are poorly understood, it needs to be further studied whether the CypA up-regulaion in cancer is controlled by the same regulatory mechanisms of stress induction.

If up-regulation of CypA in cancers is linked to p53 and HIF-1α, most well-characterized cancer-related transcriptional regulatory factors, has been sought by several groups. Choi et al. demonstrated that HIF-1α can upregulate CypA by HIF-1α binding to hypoxia response elements (HRE) in the CypA promoter region under hypoxic conditions [36]. Similarly, Gu et al. first showed that CypA is up-regulated during p53-induced apoptosis using quantitative proteomic profiling [37, 38]. They also proposed that transcription of CypA might be induced by activated p53. While no direct evidence has been reported that p53 is activated or stabilized by CypA, it is interesting to note that PIN 1, another type of PPIases, stabilizes p53 through affinity binding of PIN 1 to the p53's proline rich domain (PRD) [39]. Our group recently discovered binding activity of CypA to p53 which leads to stabilization of p53 (unpublished data).

Clinical implications of the overexpressed Cyclophilin A in cancers

Upregulation of CypA in many cancer types dictates an advantage of CypA overexpression toward cancer development. While the exact roles of CypA in cancer cells are yet to be defined, understanding the precise function of CypA during tumor development will be critical to assess its potential as a target for therapeutic intervention.

Positive growth effect by excessive CypA on cancer cells was first reported by Howard et al. They showed that overexpression of CypA in small cell lung cancer stimulates cancer cell growth, and knockdown of CypA slows cancer cell growth, independent of its effects on angiogenesis [17, 18]. Other roles of CypA have also been proposed. Qi et al. suggested that CypA is upregulated during malignant tansformation of esophageal squamous cells [32]. CypA abundance is more than 5 fold, compared to non-malignant immortalized control cell lines [40]. There also exist reports that CypA may regulate metastasis [32, 33].

During development of solid tumors, ROS are continuously generated in tumor's central hypoxic region. Hong et al. suggested that CypA has antioxidant effects through its PPIase activity [13]. It is consistent with the finding that CypA overexpression promotes cancer cell proliferation and blocks apoptosis induced by hypoxia [36]. Choi et al. showed that overexpression of CypA in cancer cells renders resistance to hypoxia- and cisplatin-induced cell death in a p53 independent manner [36].

There are several reports suggesting that inhibition of PPIase activity of CypA may generate potential chemotherapeutic effects. Yurchenko et al. has reported that cell surface expression of CD147, tumor cell-derived collagenase stimulatory factor, is regulated by CypA [41, 42]. Overexpressed CypA interacts with the proline-containing peptide in CD147's transmembrane domain and stimulates human pancreatic cancer cell proliferation [43]. Zheng et al. also demonstrated in breast cancer cells that prolactin needs to bind CypA for cancer progression and tumor metastasis [44]. Han et al. showed that CsA and sanglifehrin A (SfA), two CypA inhibitors, increase chemotherapeutic effect of cisplatin in glioblastoma multiforme [34]. Overexpression and known functional roles of CypA in various cancer types are summarized in Table 1.

Table 1 Cyclophilin A in human cancers

Other cyclophilins and cancers

Other Cyps including CypB, CypC, CypD and Cyp40 might also play important roles in carcinogenesis. Kim et al. reported that CypB protects cells against ER stress-induced cell death at least partly through blocking the Ca2+ leakage from ER to cytosol [45]. Overexpression of CypB is associated with tumor progression through regulation of hormone receptor expression and gene products involved in cell proliferation and motility [46]. Interestingly, CypB possesses two antigenic epitopes (CypB (82-92) and CypB (91-99)) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes that are suggested to be used for vaccines against cancers [47].

CypC is another Cyp family member that is primarily located in ER, but its role remains to be determined. CypC can form a complex with the COOH-terminal fragment of osteopontin. This complex binds to CD147 to activate Akt1/2 and MMP-2 in 4T07 murine breast cancer cells. This CyC- osteopontin complex regulates in vitro migration and invasion properties of 4T1 and 4T07 breast cancer cells [48].

CypD is an important component of the mitochondrial permeability transition pore, another components of which are the voltage-dependent outer membrane anion channel, adenine nucleotide translocator [49, 50], and hexokinase. PPIase activity of CypD may be necessary for binding of CypD to the MPTP complex [51]. Although function of CypD in mitochondria is controversial, overexpression of CypD attenuates sensitivity of HEK 293 and rat glioma C6 cells to apoptotic stimuli, with protective effects of CypD requiring PPIase activity [52]. Consistently, several reports have shown that CypD is overexpressed and has an anti-apoptotic effect in various tumors via a Bcl 2 collaborator and an inhibitor of cytochrome c release from mitochondria [53]. This protective effect is independent of the MPTP [53].

Cyp40 mRNA has also been reported to increase in many breast cancer cell lines including MCF-7 [54]. Additionally, Cyp40 mRNA also increases in response to high temperature stress in MCF-7 cells [55]. Up-regulation of Cyp40 is reported to be correlated with oxidative stress in MCF-7 cells and prostate cancer cell lines. Genetic analysis of breast cancers shows 30% allelic loss of Cyp40 from patients heterozygous for Cyp40 [56]. Overexpression and potential roles for other Cyps in various cancer types are summarized in Table 2.

Table 2 Other cyclophilins in human cancers


Cyps regulate protein folding through PPIase enzymatic and chaperone activities in specific locales of the cells to ensure correct conformation and to counterbalance conformational variations under diverse stress conditions. In addition to PPIase and chaperone activities, each isoform of Cyps has other specific intracellular and extracellular roles. Although roles of Cyps have recently been explored in more details, many physiological and pathological aspects of Cyps' biology still remain unclear.

CypA among the Cyps was first reported to be upregulated in tumors, including small cell lung cancer, pancreatic cancer, breast cancer, colorectal cancer, squamous cell carcinoma, glioblastoma multiforme, and melanoma. This wide spectrum of cancers harboring excess CypA denotes an important role of CypA in tumor development. The possible roles of CypA in cancers might involve increased cell proliferation, blockage of apoptosis, malignant transformation, angiogenesis, metastasis, and resistance to chemotherapeutic agents. Transcriptional upregulation of CypA mediated by p53 and HIF-1α during tumor development would magnify the cancer-prone effect of CypA.

Some groups have proposed CypA as a cancer biomarker for certain cancer subtypes because expression levels nicely correlate with tumor progression. Although less informed at now, other Cyps are also known to be overexpressed and proposed to be involved in various cancers.

CsA and SfA induce apoptosis in various cancer cells via inhibition of PPIase activity of Cyps, and have been tested for clinical applications in diverse cancer types [34]. However, CsA and Sfa can hardly be applied to cancer patients because of immunosuppressive effects. The detailed understanding on the molecular mechanisms by which Cyps affect cancer development will aid the development of new chemotherapeutic agents. Specific inhibitors of the PPIase activity of Cyps devoid of immune suppressive effects will be promising for the treatment of cancers currently resistant to available chemotherapeutics.


  1. 1.

    Fischer G, Tradler T, Zarnt T: The mode of action of peptidyl prolyl cis/trans isomerase in vivo: Binding vs catalysis. FEBS Lett. 1998, 426: 17-20. 10.1016/S0014-5793(98)00242-7.

    CAS  Article  Google Scholar 

  2. 2.

    Schmid FX: Protein folding. Prolyl isomerase join the fold. Curr Biol. 1995, 5: 993-994. 10.1016/S0960-9822(95)00197-7.

    CAS  Article  Google Scholar 

  3. 3.

    Schreiber SL: Immunophilin-sensitive protein phosphatase action in cell signaling pathways. Cell. 1992, 70: 365-368. 10.1016/0092-8674(92)90158-9.

    CAS  Article  Google Scholar 

  4. 4.

    Göthel SF, Marahiel MA: Peptidyl-prolyl cis-trans isomerase, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci. 1999, 55: 423-436. 10.1007/s000180050299.

    Article  Google Scholar 

  5. 5.

    Hunter T: Prolyl isomerase and nuclear function. Cell. 1998, 92: 141-143. 10.1016/S0092-8674(00)80906-X.

    CAS  Article  Google Scholar 

  6. 6.

    Rutherford SL, Zuker CS: Protein folding and the regulation of signaling pathways. Cell. 1994, 79: 1129-1132. 10.1016/0092-8674(94)90003-5.

    CAS  Article  Google Scholar 

  7. 7.

    Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporine A and FKBP-FK506 complexes. Cell. 1991, 66: 807-815. 10.1016/0092-8674(91)90124-H.

    CAS  Article  Google Scholar 

  8. 8.

    Galat A: Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity targets functions. Curr Top Med Chem. 2003, 3: 1315-1347. 10.2174/1568026033451862.

    CAS  Article  Google Scholar 

  9. 9.

    Anderson SK, Gallinger S, Roder J, Frey J, Young HA, Ortaldo JR: A cyclophilin-related protein involved in the function of natural killer cells. Proc Natl Acad Sci USA. 1993, 90: 542-546. 10.1073/pnas.90.2.542.

    CAS  Article  Google Scholar 

  10. 10.

    Towers GJ, Hatziioannou T, Cowan S, Goff SP, Luban J, Bieniasz PD: Cyclophilin A modelates the sensitivity of HIV-1 to host restriction factors. Nat Med. 2003, 9: 1138-1143. 10.1038/nm910.

    CAS  Article  Google Scholar 

  11. 11.

    Wohlfarth C, Efferth T: Natural products as promising drug candidates for the treatment of hepatitis B and C. Acta Pharmacol Sin. 2009, 30 (1): 25-30. 10.1038/aps.2008.5.

    CAS  Article  Google Scholar 

  12. 12.

    Satoh K, Nigro P, Berk BC: Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin a. Antioxid Redox Signal. 2010, 1:12 (5): 675-682. 10.1089/ars.2009.2875.

    Article  Google Scholar 

  13. 13.

    Hong F, Lee J, Song JW, Lee SJ, Ahn H, Cho JJ, Ha J, Kim SS: Cyclosporine A blocks muscle differentiation by inducing oxidative stress and inhibiting the peptidyl-prolyl-cis-trans isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporine A-induced cytotoxicity. FASEB J. 2002, 16: 1633-1635.

    CAS  Google Scholar 

  14. 14.

    Wiederrecht G, Lam E, Hung S, Martin M, Sigal N: The mechanism of action of FK- 506 and cyclosporine A. Ann NY Acad Sci. 1993, 696: 9-19. 10.1111/j.1749-6632.1993.tb17137.x.

    CAS  Article  Google Scholar 

  15. 15.

    Corton JC, Moreno ES, Merritt A, Bocos C, Cattley RC: Cloning genes responsive to a hepatocarcinogenic peroxisome proliferator chemical reveals novel targets of regulation. Cancer Lett. 1998, 134: 61-71. 10.1016/S0304-3835(98)00241-9.

    CAS  Article  Google Scholar 

  16. 16.

    Lim SO, Park SJ, Kim W, Park SG, Kim HJ, Kim YI, Sohn TS, Noh JH, Jung G: Proteome analysis of hepatocellular carcinoma. Biochem Biophys Res Commun. 2002, 291: 1031-1037. 10.1006/bbrc.2002.6547.

    CAS  Article  Google Scholar 

  17. 17.

    Howard BA, Zheng Z, Campa MJ, Wang MZ, Sharma A, Haura E, Herndon JE, Fitzgerald MC, Bepler G, Patz EF: Translating biomarkers into clinical practice: prognostic implications of cyclophilin A and macrophage migratory inhibitory factor identified from protein expression profiles in non-small cell lung cancer. Lung Cancer. 2004, 46: 313-323. 10.1016/j.lungcan.2004.05.013.

    Article  Google Scholar 

  18. 18.

    Howard BA, Furumai R, Campa MJ, Rabbani ZN, Vujaskovic Z, Wang XF, Patz EF: Stable RNA interference-mediated suppression of cyclophilin A diminishes non-small-cell lung tumor growth in vivo. Cancer Res. 2005, 65: 8853-8860. 10.1158/0008-5472.CAN-05-1219.

    CAS  Article  Google Scholar 

  19. 19.

    Yang H, Chen J, Yang J, Qiao S, Zhao S, Yu L: Cyclophilin A is upregulated in small cell lung cancer and activates ERK1/2 signal. Biochem Biophys Res Commun. 2007, 361: 763-767. 10.1016/j.bbrc.2007.07.085.

    CAS  Article  Google Scholar 

  20. 20.

    Campa MJ, Wang MZ, Howard B, Fitzgerald MC, Patz EF: Protein expression profiling identifies macrophage migration inhibitory factor and cyclophilin a as potential molecular targets in non-small cell lung cancer. Cancer Res. 2003, 63: 1652-1656.

    CAS  Google Scholar 

  21. 21.

    Cecconi D, Astner H, Donadelli M, Palmieri M, Missiaglia E, Hamdan M, Scarpa A, Righetti PG: Proteomic analysis of pancreatic ductal carcinoma cells treated with 5-aza-2'-deoxycytidine. Electrophoresis. 2003, 24: 4291-4303. 10.1002/elps.200305724.

    CAS  Article  Google Scholar 

  22. 22.

    Shen J, Person MD, Zhu J, Abbruzzese JL, Li D: Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res. 2004, 64: 9018-9026. 10.1158/0008-5472.CAN-04-3262.

    CAS  Article  Google Scholar 

  23. 23.

    Li M, Wang H, Li F, Fisher WE, Chen C, Yao Q: Effect of cyclophilin A on gene expression in human pancreatic cancer cells. Am J Surg. 2005, 190: 739-745. 10.1016/j.amjsurg.2005.07.013.

    CAS  Article  Google Scholar 

  24. 24.

    Li M, Zhai Q, Bharadwaj U, Wang H, Li F, Fisher WE, Chen C, Yao Q: Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. Cancer. 2006, 106: 2284-2294. 10.1002/cncr.21862.

    CAS  Article  Google Scholar 

  25. 25.

    Mikuriya K, Kuramitsu Y, Ryozawa S, Fujimoto M, Mori S, Oka M, Hamano K, Okita K, Sakaida I, Nakamura K: Expression of glycolytic enzymes is increased in pancreatic cancerous tissues as evidenced by proteomic profiling by two-dimensional electrophoresis and liquid chromatography-mass spectrometry/mass spectrometry. Int J Oncol. 2007, 30: 849-855.

    CAS  Google Scholar 

  26. 26.

    Zheng J, Koblinski JE, Dutson LV, Feeney YB, Clevenger CV: Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer. Cancer Res. 2008, 68: 7769-7778. 10.1158/0008-5472.CAN-08-0639.

    CAS  Article  Google Scholar 

  27. 27.

    Hathout Y, Riordan K, Gehrmann M, Fenselau C: Differential protein expression in the cytosol fraction of an MCF-7 breast cancer cell line selected for resistance toward melphalan. J Proteome Res. 2002, 1: 435-442. 10.1021/pr020006i.

    CAS  Article  Google Scholar 

  28. 28.

    Melle C, Osterloh D, Ernst G, Schimmel B, Bleul A, von Eggeling F: Identification of proteins from colorectal cancer tissue by two-dimensional gel electrophoresis and SELDI mass spectrometry. Int J Mol Med. 2005, 16: 11-17.

    CAS  Google Scholar 

  29. 29.

    Lou J, Fatima N, Xiao Z, Stauffer S, Smythers G, Greenwald P, Ali IU: Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells. Cancer Epidemiol Biomarkers Prev. 2006, 15: 1598-1606. 10.1158/1055-9965.EPI-06-0216.

    CAS  Article  Google Scholar 

  30. 30.

    Wong CS, Wong VW, Chan CM, Ma BB, Hui EP, Wong MC, Lam MY, Au TC, Chan WH, Cheuk W, Chan AT: Identification of 5-fluorouracil response proteins in colorectal carcinoma cell line SW480 by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Oncol Rep. 2008, 20: 89-98.

    CAS  Google Scholar 

  31. 31.

    Chen J, He QY, Yuen AP, Chiu JF: Proteomics of buccal squamous cell carcinoma: the involvement of multiple pathways in tumorigenesis. Proteomics. 2004, 24: 2465-2475. 10.1002/pmic.200300762.

    Article  Google Scholar 

  32. 32.

    Qi YJ, He QY, Ma YF, Du YW, Liu GC, Li YJ, Tsao GS, Ngai SM, Chiu JF: Proteomic identification of malignant transformation-related proteins in esophageal squamous cell carcinoma. J Cell Biochem. 2008, 104: 1625-1635. 10.1002/jcb.21727.

    CAS  Article  Google Scholar 

  33. 33.

    Al-Ghoul M, Brück TB, Lauer-Fields JL, Asirvatham VS, Zapata C, Kerr RG, Fields GB: Comparative proteomic analysis of matched primary and metastatic melanoma cell lines. J Proteome Res. 2008, 27: 4107-4118. 10.1021/pr800174k.

    Article  Google Scholar 

  34. 34.

    Han X, Yoon SH, Ding Y, Choi TG, Choi WJ, Kim YH, Kim YJ, Huh YB, Ha J, Kim SS: Cyclosproin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells. Oncol Rep. 2010, 23: 1053-1062. 10.3892/or_00000816.

    CAS  Article  Google Scholar 

  35. 35.

    Weisinger G, Gavish M, Mazurika C, Zinder O: Transcription of actin, cyclophilin and glyceraldehyde phosphate dehydrogenase genes: Tissue- and treatment-specificity. Biochimica et Biophysica Acta - Gene Structure and Expression. 1999, 1446 (3): 225-232. 10.1016/S0167-4781(99)00091-3.

    CAS  Article  Google Scholar 

  36. 36.

    Choi KJ, Piao YJ, Lim MJ, Kim JH, Ha J, Choe W, Kim SS: Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia- and cisplatin-induced cell death. Cancer Res. 2007, 67: 3654-3662. 10.1158/0008-5472.CAN-06-1759.

    CAS  Article  Google Scholar 

  37. 37.

    Gu S, Liu Z, Pan S, Jiang Z, Lu H, Amit O, Bradbury EM, Hu C A, Chen X: Global investigation of p53-induced apoptosis through quantitative proteomic profiling using comparative amino acid-coded tagging. Mol Cell Proteomics. 2004, 3: 998-1008. 10.1074/mcp.M400033-MCP200.

    CAS  Article  Google Scholar 

  38. 38.

    Yu X, Harris SL, Levine AJ: The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006, 66: 4795-4801. 10.1158/0008-5472.CAN-05-4579.

    CAS  Article  Google Scholar 

  39. 39.

    Mantovani F, Tocco F, Girardini J, Smith P, Gasco M, Lu X, Crook T, Del Sal G: The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nat Struct Mol Biol. 2007, 14: 912-920. 10.1038/nsmb1306.

    CAS  Article  Google Scholar 

  40. 40.

    Chaurand P, Rahman MA, Hunt T, Mobley JA, Gu G, Latham JC, Caprioli RM, Kasper S: Monitoring mouse prostate development by profiling and imaging mass spectrometry. Molecular & Cellular Proteomics. 2008, 7: 411-423.

    CAS  Article  Google Scholar 

  41. 41.

    Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K: The human tumor cell derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res. 1995, 55: 434-439.

    CAS  Google Scholar 

  42. 42.

    Yurchenko V, Pushkarsky T, Li JH, Dai WW, Sherry B, Bukrinsky M: Regulation of CD147 cell surface expression: involvement of the proline residue in the CD147 transmembrane domain. J Biol Chem. 2005, 280: 17013-17019. 10.1074/jbc.M412851200.

    CAS  Article  Google Scholar 

  43. 43.

    Boulos S, Meloni BP, Arthur PG, Majda B, Bojarski C, Knuckey NW: Evidence that intracellular cyclophilin A and cyclophilin A/CD147 receptor-mediated ERK1/2 signalling can protect neurons against in vitro oxidative and ischemic injury. Neurobiol Dis. 2006, 25: 54-64. 10.1016/j.nbd.2006.08.012.

    Article  Google Scholar 

  44. 44.

    Zheng J, Koblinski JE, Dutson LV, Feeney YB, Clevenger CV: Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer. Cancer Res. 2008, 68: 7769-7778. 10.1158/0008-5472.CAN-08-0639.

    CAS  Article  Google Scholar 

  45. 45.

    Kim J, Choi TG, Ding Y, Kim Y, Ha KS, Lee KH, Kang I, Ha J, Kaufman RJ, Lee J, Choe W, Kim SS: Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca2+ homeostasis after ER stress. J Cell Sci. 2008, 121: 3636-364. 10.1242/jcs.028654.

    CAS  Article  Google Scholar 

  46. 46.

    Fang F, Flegler AJ, Du P, Lin S, Clevenger CV: Expression of cyclophilin B is associated progression and regulation with malignant of genes implicated in pathogenesis of breast cancer. Am J Pathol. 2009, 174 (1): 297-308. 10.2353/ajpath.2009.080753.

    CAS  Article  Google Scholar 

  47. 47.

    Gomi S, Nakao M, Niiya F, Imamura Y, Kawano K, Nishizaka S, Hayashi A, Sobao Y, Oizumi K, Itoh K: A cyclophilin B gene encodes antigenic epitopes recognized by HLA-A24-restricted and tumorspecific CTLs. J Immunol. 1999, 163: 4994-5004.

    CAS  Google Scholar 

  48. 48.

    Mi Z, Oliver T, Guo H, Gao C, Kuo PC: Thrombin-cleaved COOH-terminal osteopontin peptide binds with cyclophilin C to CD147 in murine breast cancer cells. Cancer Res. 2007, 67: 4088-4097. 10.1158/0008-5472.CAN-06-4066.

    CAS  Article  Google Scholar 

  49. 49.

    Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Rémy R, Xie ZH, Reed JC, Kroemer G: The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2- related proteins. J Exp Med. 1998, 187: 1261-1271. 10.1084/jem.187.8.1261.

    CAS  Article  Google Scholar 

  50. 50.

    Lin DT, Lechleiter JD: Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization. J Biol Chem. 2002, 277: 31134-31141. 10.1074/jbc.M112035200.

    CAS  Article  Google Scholar 

  51. 51.

    Halestrap A: Biochemistry: A pore way to die. Nature. 2005, 434: 578-579. 10.1038/434578a.

    CAS  Article  Google Scholar 

  52. 52.

    Tanveer A, Virji S, Andreeva L, Totty NF, Hsuan JJ, Ward JM, Crompton M: Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur Biochem J. 1996, 238: 166-172. 10.1111/j.1432-1033.1996.0166q.x.

    CAS  Article  Google Scholar 

  53. 53.

    Eliseev RA, Malecki J, Lester T, Zhang Y, Humphrey J, Gunter TE: Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J Biol Chem. 2009, 284: 9692-9699. 10.1074/jbc.M808750200.

    CAS  Article  Google Scholar 

  54. 54.

    Ward BK, Mark PJ, Ingram DM, Minchin RF, Ratajczak T: Expression of the estrogen receptor-associated immunophilins, cyclophilin 40 and FKBP52, in breast cancer. Breast Cancer Res Treat. 1999, 58: 267-280. 10.1023/A:1006390804515.

    CAS  Article  Google Scholar 

  55. 55.

    Mark PJ, Ward BK, Kumar P, Lahooti H, Minchin RF, Ratajczak T: Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock. Cell Stress Chaperones. 2001, 6: 59-70. 10.1379/1466-1268(2001)006<0059:HCIAHS>2.0.CO;2.

    CAS  Article  Google Scholar 

  56. 56.

    Ward BK, Kumar P, Turbett GR, Edmondston JE, Papadimitriou JM, Laing NG, Ingram DM, Minchin RF, Ratajczak T: Allelic loss of cyclophilin 40, an estrogen receptor-associated immunophilin, in breast carcinomas. J Cancer Res Clin Oncol. 2001, 127: 109-115. 10.1007/s004320000182.

    CAS  Article  Google Scholar 

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This work was supported by grants from the Korean Government (MEST, No.20090091346).

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Lee, J., Kim, S.S. Current implications of cyclophilins in human cancers. J Exp Clin Cancer Res 29, 97 (2010).

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  • Small Cell Lung Cancer
  • Glioblastoma Multiforme
  • Chaperone Activity
  • CypA Expression
  • PPIase Activity