Beta 1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway.
BACKGROUND
beta 1-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 beta 1-integrin in the disease process of HCC is not fully understood. The authors investigated the effects of beta 1-integrin on apoptosis in hepatoma cells.


METHODS
Human hepatoma cell lines HepG2, Huh7, and HLE were stably transfected with full-length beta 1-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 beta 1-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 beta 1-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 beta 1-integrin. Neither herbimycin nor wortmannin blocked the protective effects of beta 1-integrin overexpression.


CONCLUSIONS
These data suggest that overexpression of beta 1-integrin confers resistance to apoptosis in hepatoma cells via a MAP kinase dependent pathway. beta1-integrin mediated signaling from the ECM in HCC cells may contribute to chemotherapy resistance.
Zhang
Hao
H
Division of Hepatology and Metabolism, Department of Internal Medicine, Saga Medical School, Saga, Japan.
Ozaki
Iwata
I
Mizuta
Toshihiko
T
Matsuhashi
Sachiko
S
Yoshimura
Tohru
T
Hisatomi
Akitaka
A
Tadano
Jutaro
J
Sakai
Takahiro
T
Yamamoto
Kyosuke
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D019012:Integrin beta1