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.

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].