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Table 3 Summary of the expression changes of apoptosis related genes for the single substances (TRD 250 μmol/l, TRAIL 50 ng/ml) compared to untreated cells and the combination therapy compared to Control, TRD and TRAIL treated cells.

From: TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

Gene Symbol Gene Title Synonyms Gene function
NFKBIA nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha IkappaB-alpha, IkB-a, IkBa, Inhibitor of kappa B-alpha, MAD3, P40 Proliferation in HT1080 cells is mediated through a NFKB dependent pathways [29, 54].
Tumor invasiveness could be significantly reduced in HT1080 cells by reducing NFKB activity [30].
Increased NFKB activity leads to doxorubicin resistance in a p53 dependent manner [28].
HSPA1A/B heat shock 70 kDa protein 1A/B HSP70, HSP72, HSPA1 Upregulation of HSPA1A significantly increased chemosensitivity of HT1080 to mitomycin C [34].
The apoptogenic effects of taxanes on sarcoma could be increased by co-therapy with stimulators of HSPA1A expression [35].
SGK serum/glucocorticoid regulated kinase serine/threonine-protein kinase Sgk1, serum/glucocorticoid-regulated kinase 1, SGK1 SGK activates the NFKB pathway and thereby can prevent cells from undergoing apoptosis [42].
GADD45A growth arrest and DNA-damage-inducible, alpha DDIT1, DNA-damage-inducible transcript 1, GADD45, Growth arrest and DNA-damage-inducible protein, GADD45 alpha Upregulation of GADD45A is associated with increased apoptosis and cell cycle arrest p53 independently in a variety of soft tissue sarcomas [37].
It inhibits transcription factors associated with tumor growth including the c-Jun N-terminal kinase (JNK) cascade and NFKB [38, 39, 41, 55].
For rhabdomyosarcoma, increased GADD45A expression was associated with less aggressive tumor behaviour [40].
GADD45 may antagonize TNF-receptor mediated cytotoxicity [41].
ARHGDIA Rho GDP dissociation inhibitor (GDI) alpha GDIA1, MGC117248, RHOGDI, Rho GDI 1, Rho-GDI alpha, Rho GDP-dissociation inhibitor 1 High levels of Rho-GTP are detected in HT1080 cells. The inhibition of Rho by fasudil, a Rho kinase inhibitor lead to decreased tumor cell motility and growth in HT1080 cells [25] and associated to the development of metastases in several other malignant tumors [23, 24].
ARHGDIA is downregulated by doxorubicin in HT1080 cells [56].
PPP1R15A protein phosphatase 1, regulatory (inhibitor) subunit 15A GADD34, MyD116 Increased expression of PPP1R15A by chemosensitizers can potentiate the effects of cytostatics such as platinum agents [57] and probably acts p53 independently [58].
MYC v-myc myelocytomatosis viral oncogene homolog (avian) c-Myc, Myc proto-oncogene protein, transcription factor p64 Myc induces apoptosis by increasing the p53 levels JNK-dependently [59].
AXL AXL receptor tyrosine kinase oncogene tyrosine-protein kinase receptor UFO precursor, UFO AXL is associated with metastatic potential of malignant cells by regulating adherence, motility, and invasiveness [60].
It can prevent cells from TNFalpha mediated cell death via the phosphatidylinositol 3-kinase [61] and the NFKB pathway [62].
MAP3K14 mitogen-activated protein kinase kinase kinase 14 FTDCR1B, HS, HsNIK, HSNIK, mitogen-activated protein kinase kinase kinase 14, NF-kappa beta-inducing kinase, NIK, serine/threonine-protein kinase NIK MAP3K14 is a member of the TNF-Pathway and activates NFKB (IKKalpha) [46]. The MAPkinase pathway can induce apoptosis by induction of the GADD family of genes (GADD 34, GADD 45) [63].
BIRC3 baculoviral IAP repeat-containing 3 AIP1, API2, apoptosis inhibitor 2, Baculoviral IAP repeat-containing protein 3, cIAP2, CIAP2, C-IAP2, HAIP1, HIAP1, hiap-1, HIAP-1, IAP1, IAP homolog C, inhibitor of apoptosis protein 1, MALT2, MIHC, RNF49, TNFR2-TRAF signalling complex protein 1 BIRC3 is associated with chemotherapy resistance in Ewing sarcoma, rhabdomyosarcoma [64] and prostatic cancer [65] and suppresses TNFalpha mediated cell death by preventing formation of TNF Receptor 1. It regulates pro-survival NFKB-signalling by promoting degradation of MAP3K14 [66].
CALR calreticulin calregulin, calreticulin precursor, cC1qR, CRP55, CRTC, ERp60, FLJ26680, grp60, HACBP, RO, SSA Calreticulin belongs to the family of heat shock proteins and strongly binds to TRAIL [67]. Calreticulin is translocated to tumor cells' membranes after anthracyline therapy and stimulates the anti-tumor immune response [68].
DUSP1 dual specificity phosphatase 1 CL100, dual specificity protein phosphatase 1, dual specificity protein phosphatase hVH1, HVH1, MAP kinase phosphatase 1, MKP1, MKP-1, protein-tyrosine phosphatase CL100, PTPN10, VH1 DUSP inactivates MAP kinases [69] and can protect cells from apoptotic stimuli by chemotherapeutics [70].
JUN v-jun sarcoma virus 17 oncogene homolog activator protein 1, AP1, p39, proto-oncogene c-jun, transcription factor AP-1, V-jun avian sarcoma virus 17 oncogene homolog Jun is activated by TRAIL JNK dependently and promotes apoptotic cell death in malignant cells including osteosarcoma [43].
Downregulation of JUN decreases the expression of matrix metalloproteinases and thereby cellular invasiveness in HT1080 cells [44]. This down-regulation may be mediated through suppression off NFKB activation [45].
JUN is known to be a product of MAP2K4-activation and to mediate apoptosis by several chemotherapeutics [55].
upregulation of HSPA1A and JUN expression Chemosensitivity of HT1080 to mitomycin C could significantly be increased by [34].
IRF1 interferon regulatory factor 1 MAR IRF1 inhibits cell growth and induces apoptosis via activation of caspases 1 and 7 [71]. It inhibits NFKB-dependent activation of matrix metalloproteinase-9 (MMP9) [72].
TNFAIP3 tumor necrosis factor, alpha-induced protein 3 A20, MGC104522, MGC138687, MGC138688, Putative DNA-binding protein A20, TNFA1P2, Zinc finger protein A20 TNFAIP3 down-regulates the TNF-α-induced NFKB signalling pathway [26] and reduces TNF mediated apoptosis and necrosis [27].
BAG5 BCL2-associated athanogene 5 BAG-5, BAG family molecular chaperone regulator 5, KIAA0873 BAG family members inhibit Hsp70 and promote cell growth and survival [73].
CLK4 CDC-like kinase 4 Dual specificity protein kinase CLK4 CLK family members prevent cells from undergoing intrinsic apoptosis [74].
MET met proto-oncogene (hepatocyte growth factor receptor) c-Met, Hepatocyte growth factor receptor precursor, HGF/SF receptor, HGFR, HGF receptor, Met proto-oncogene tyrosine kinase, RCCP2, Scatter factor receptor, SF receptor Over-expression of MET was associated with enhanced proliferation and aggressive tumor biology in sarcomas[75]. Survival, anchorage dependent growth and invasiveness of sarcoma cells are dependent on MET [76].
MCL1 Myeloid cell leukemia sequence 1 (BCL2-related) Bcl-2-related protein EAT/mcl1, EAT, Induced myeloid leukemia cell differentiation protein Mcl-1, mcl1/EAT, MCL1L, MCL1S, MGC104264, MGC1839, TM MCL1 is expressed in a variety of soft tissue sarcomas and acts anti-apoptotic. Inhibition of MCL1 in combination with low dose cyclophosphamide significantly increases apoptosis in HT1080 cells [47].
MAP3K1 mitogen-activated protein kinase kinase kinase 1 MAPK/ERK kinase kinase 1, MAPKKK1, MEKK, MEKK1, MEKK 1, MEK kinase 1 MEKK is activating MAPK and JNK. Reduction of MEKK activity amplifies the apoptotic effect of TNFalpha on fibrosarcoma cells [77].
CASP2 caspase 2, apoptosis-related cysteine peptidase (neural precursor cell expressed, developmentally down-regulated 2) apoptosis-related cysteine peptidase (neural precursor cell expressed, developmentally down-regulated 2), CASP-2, Caspase-2 precursor, ICH1, ICH-1L, ICH-1L/1S, ICH-1 protease, NEDD2 Casp2 is a member of the caspases family and mediates apoptotic cell death NFKB and Jun dependently but independent from Fas [78].
  1. Signal log ratios of the changes are given for the several samples (TRD vs control, TRAIL vs control, TRD/TRAIL vs control, TRD/TRAIL vs TRD), signal log ratio of 1 representing a twofold increase, one of -1, that the expression is half of the expression of the control group and so forth.