G-protein alpha(olf) subunit promotes cellular invasion, survival, and neuroendocrine differentiation in digestive and urogenital epithelial cells.
The heterotrimeric G-protein subunits Galpha and Gbetagamma are involved in cellular transformation and tumor development. Here, we report the expression of Galpha(olf) in human digestive and urogenital epithelial cells using RT-PCR and Western blot. When the constitutively activated form of Galpha(olf)Q214L (AGalpha(olf)) was stably transfected in canine kidney MDCKts.src and human colonic HCT-8/S11 epithelial cells, it induced cellular invasion in collagen gels. AGalpha(olf)-mediated invasion was abrogated by agonists of platelet activating factor receptors (PAF-R) and protease-activated receptors -1 (PAR-1), pharmacological inhibitors of PI3'-Kinase (wortmannin), protein kinase C (Gö6976 and GF109203X), Rho GTPase (C3T exoenzyme), but was independent of protein kinase A. Accordingly, the invasive phenotype induced by AGalpha(olf) in HCT-8/S11 cells was reversed by the RhoA antagonist RhoD (G26V). Although AGalpha(olf) protected MDCKts.src cells against serum starvation-mediated apoptosis via a Rho-independent pathway, both AGalpha(olf) and Rho inhibition by C3T induced neuroendocrine-like differentiation linked to extensive neurite outgrowth and parathyroid hormone-related protein expression in human prostatic LNCaP-AGalpha(olf) cells. Since prostate tumors with a larger neuroendocrine cell population display increased invasiveness, persistent activation of the G-protein alpha(olf) may exert convergent adverse effects on cellular invasion and survival in solid tumors during the neoplastic progression towards metastasis. doi:10.1038/sj.onc.1205498
Régnauld
Karine
K
INSERM U482, Signal transduction and cellular functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
Nguyen
Quang-Dé
QD
Vakaet
Luc
L
Bruyneel
Erik
E
Launay
Jean-Marie
JM
Endo
Takeshi
T
Mareel
Marc
M
Gespach
Christian
C
Emami
Shahin
S
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D003106:Colon / Q000166:cytology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004847:Epithelial Cells / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits; D006133:Growth Substances / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D009490:Neurosecretory Systems / Q000502:physiology; D009831:Olfactory Mucosa; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D017931:DNA Primers; D044385:GTP-Binding Protein alpha Subunits; D006133:Growth Substances; D011506:Proteins; C084618:olfactory G protein subunit alpha olf; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; C105243:RHOD protein, human; D020962:Heterotrimeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein