Suppression of anoikis by v-Src but not by activated c-H-ras in human gallbladder epithelial cells.
Detachment of anchorage-dependent normal epithelial cells from their substratum causes the type of apoptosis known as anoikis, whereas malignant cells can proliferate independently of anchorage. Because src and ras oncogenes are activated in many human cancers, we investigated their role and downstream signaling pathways in anoikis resistance, using HAG-1 human epithelial cells transfected with v-src or activated H-ras. Consequently, anchorage-dependent mock- or ras-transfected cells underwent anoikis. In contrast, anchorage-independent v-Src-transformed cells did not exhibit such apoptotic features. Focal adhesion kinase (FAK), a transducer of integrin, was only activated in v-Src-transformed cells. Herbimycin A, an Src kinase inhibitor, reduced tyrosyl phosphorylation of FAK and reversed resistance to anoikis. However, both protein kinase C (PKC) and phophatidylinositol-3 (PI-3) kinase inhibitors failed to induce anoikis. These data suggest that the ability of activated Src to prevent anoikis may be mediated by Src to a downstream signaling pathway involving FAK, but not Ras, PI-3 kinase, or PKC.
Hisano
Chizuko
C
First Department of Internal Medicine and Department of Medicine and Biosystemic Science, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Tanaka
Risa
R
Fujishima
Hiromitsu
H
Ariyama
Hiroshi
H
Tsuchiya
Tanji
T
Tatsumoto
Takashi
T
Mitsugi
Kenji
K
Nakamura
Minoru
M
Nakano
Shuji
S
D023102:Anoikis / Q000235:genetics*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D011905:Genes, ras / Q000235:genetics / Q000502:physiology; D016391:Genes, src / Q000235:genetics / Q000502:physiology*; D006801:Humans
D004791:Enzyme Inhibitors