β1‐integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen‐activated protein kinase dependent pathway

Abstract

BACKGROUND β1-integrin modulates cellular phenotype by mediating signals from the extracellular matrix (ECM). Although overexpression of integrin molecules in hepatocellular carcinoma (HCC) has been reported, the role of overexpressed β1-integrin in the disease process of HCC is not fully understood. The authors investigated the effects of β1-integrin on apoptosis in hepatoma cells. METHODS Human hepatoma cell lines HepG2, Huh7, and HLE were stably transfected with full-length β1-integrin. Cells underwent apoptosis induced by chemotherapeutic reagents, including cis-platinum (II)-diammine dichloride, etoposide, and docetaxel. Cell survival and intracellular signaling pathways dependent on β1-integrin-mediated apoptosis effects were analyzed by treating cells with PD98059 (ERK inhibitor), SB203580 (p38MAP kinase inhibitor), wortmannin (phosphatidyl inositol-3-kinase inhibitor), and herbimycin A (tyrosine kinase inhibitor). RESULTS All three hepatoma cell lines overexpressing β1-integrin were protected from apoptosis induced by chemotherapeutic reagents, whereas parental or mock transfected cells were not. Treatment with PD98059 or SB203580 abolished the protective effect on apoptosis in cells overexpressing β1-integrin. Neither herbimycin nor wortmannin blocked the protective effects of β1-integrin overexpression. CONCLUSIONS These data suggest that overexpression of β1-integrin confers resistance to apoptosis in hepatoma cells via a MAP kinase dependent pathway. β1-integrin mediated signaling from the ECM in HCC cells may contribute to chemotherapy resistance. Cancer 2002;95:896–906. © 2002 American Cancer Society. DOI 10.1002/cncr.10751