Cross-talk between Epidermal Growth Factor Receptor and Hypoxia-inducible Factor-1α Signal Pathways Increases Resistance to Apoptosis by Up-regulating Survivin Gene Expression

Abstract

Although increasing evidence supports a link between epidermal growth factor receptor (EGFR) signaling and resistance to apoptosis, the mechanism by which the EGFR signaling pathway inhibits apoptosis is not well understood. In this study, we found that epidermal growth factor ( The EGFR 2 signaling pathway plays a key role in the regulation of cell proliferation, survival, and differentiation (1, 2). It has been shown that the level of EGFR is up-regulated in many human tumor tissues. Activation of EGFR signaling has been associated with highly aggressive cancer types and poor responses to therapeutic agents (3-7). Prior preclinical and clinical studies have shown that blocking the EGFR signaling via monoclonal antibodies or inhibition of the EGFR tyrosine kinase with small molecules reduces the growth of breast cancers and sensitizes responses to chemotherapy (8 -10).Recently, we and others have shown that activation of the EGFR signaling pathway leads to the up-regulation of survivin, a member of the inhibitor of apoptosis (IAP) protein family (11)(12)(13)(14). Survivin is broadly expressed in fetal tissues but is undetectable in the most normal adult tissues (15). However, a high level of survivin is found in most common tumor types, including over 70% of human breast cancer tissues at all stages of cancer development (16 -18). It has been shown that in breast cancer cells, levels of survivin expression correlate with susceptibility to apoptosis (17). At present, the mechanism by which this up-regulation of survivin occurs in tumor cells having activated EGFR signaling is not fully understood. Recent studies have suggested, however, that activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway by EGFR signaling causes up-regulation of survivin expression (12, 13). It is still unknown how PI3K/AKT signaling leads to survivin gene transcription.Several studies have shown that under normoxic conditions, activation of EGFR signaling also increases the level of hypoxiainducible factor 1␣ (HIF-1␣) through the PI3K/AKT pathway (19 -21). HIF-1␣, a member of the basic helix-loop-helix-PAS protein family (22) 2 The abbreviations used are: EGFR, epidermal growth factor receptor; IAP, inhibitor of apoptosis; EGF, epidermal growth factor; HIF, hypoxia-inducible factor; Doc, docetaxel; HRE, hypoxia-responsive element; 7-AAD, 7-amino-actinomycin D; PI3K, phosphoinositide 3-kinase; siRNA, small interfering RNA; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PE, phycoerythrin; nt, nucleotide(s); MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor.

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

“…In addition, cell survival and cell death are both regulated by hypoxia, in part through the regulation of programmed cell death I and II processes named apoptosis and autophagy respectively. The regulation of apoptosis by hypoxia involves the regulation of the expression of genes such as Bid, Bax, Noxa, Survivin and Mcl-1 [5][6][7][8]. In addition, hypoxia selects cancer cells with reduced apoptotic potential [9].…”

Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

“…Irradiation induces the expression of HIF‐1α, while the latter in turn causes radioresistance by triggering several signaling pathways. HIF‐1α inhibited the apoptosis of malignant cells,45, 46 induced γH2AX expression and hypoxic condition, enhanced DNA repair and finally led to the poor response of tumor treatment 47…”

The effects of knockdown of wild-type survivin, survivin-2B or survivin-Δ3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions

“…Additionally, Ueda et al 45 demonstrated that hypoxia under serum-starved conditions lead to increased survivin expression in human brain microvascular endothelial cells and EGF stimulation in breast cancer cell lines resulted in an upregulation of survivin. 46 This was caused by direct binding and activation of the survivin promoter by the hypoxia-inducible factor (Hif-1a). 46 In this line, knockdown of Hif-1a inhibited the expression of survivin in a pancreatic cancer cell line under hypoxic conditions.…”

“…46 This was caused by direct binding and activation of the survivin promoter by the hypoxia-inducible factor (Hif-1a). 46 In this line, knockdown of Hif-1a inhibited the expression of survivin in a pancreatic cancer cell line under hypoxic conditions. 47 In contrast, hypoxia or reoxygenation activated the PI3K/Akt pathway and lead to an upregulation of XIAP but not of survivin in renal epithelial cells.…”