Reg IV Activates the Epidermal Growth Factor Receptor/Akt/AP-1 Signaling Pathway in Colon Adenocarcinomas

Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy

“…In the present study, Reg IV expression in primary tumors was associated with response to 5-FU/cisplatin combination chemotherapy in recurrent GC cases. Although we did not evaluate activation of AP-1 in the present study, EGFRdependent activation of AP-1 by Reg IV has been reported (Bishnupuri et al, 2006). Because DPD is a downstream target gene of AP-1 (Ukon et al, 2005), phosphorylation of EGFR may be required for induction of DPD by Reg IV.…”

“…Increased Bcl-2 by forced Reg IV expression may act to inhibit the mitochondrial apoptotic pathway. Bcl-2 induction by Reg IV is blocked by AG1478, a tyrosine kinase inhibitor specific for EGFR (Bishnupuri et al, 2006), indicating that phosphorylation of EGFR is required for Bcl-2 induction and that EGFR plays an important role in inhibition of apoptosis by Reg IV. In the present study, immunohistochemical analysis of GC tissues revealed that almost all EGFR-positive GC cases (92.5%) also expressed Reg IV and that EGFR was phosphorylated at Tyr 992 in all EGFR-positive GC cases.…”

“…In addition, HCT116 and HT29 colon cancer cell lines treated with recombinant Reg IV showed increased expression of Bcl-2 (Bishnupuri et al, 2006). Bcl-2 is an antiapoptotic protein located on mitochondria and expressed at high levels in some tumor cells and tissues (Vander Heiden and Thompson, 1999).…”

“…and Akt at Thr 308 and Ser 473 , resulting in increased AP-1 transcription factor activity (Bishnupuri et al, 2006). In addition, HCT116 and HT29 colon cancer cell lines treated with recombinant Reg IV showed increased expression of Bcl-2 (Bishnupuri et al, 2006).…”

“…Involvement of REG4 in drug resistance has been suggested, but the detailed mechanism remains unclear (Violette et al, 2003). A more recent study revealed that Reg IV is a potent activator of the epidermal growth factor receptor (EGFR)/Akt/activator protein-1 (AP-1) signaling pathway and those colon cancer cell lines treated with recombinant Reg IV showed increased expression of Bcl-2, Bcl-xl and survivin, which are proteins associated with inhibition of apoptosis (Bishnupuri et al, 2006). EGFR activation modulates apoptotic susceptibility (reviewed by Kari et al, 2003), and we have shown that EGFR is overexpressed in GC (Yasui et al, 1988).…”