Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling.
Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and up-regulates proinvasive integrin alpha6beta4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3 as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3 cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3 and Bad. The prosurvival effects of PTHrP are accompanied by increases in the ratio of antiapoptotic to proapoptotic members of the Bcl-2 family and in levels of c-myc. PTHrP also increases nuclear factor-kappaB activity via a PI3K-dependent pathway. Integrin alpha6beta4 is known to activate PI3K. Here, we also show that knockdown of integrin alpha6beta4 negates the PTHrP-mediated activation of the PI3K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3K/Akt signaling pathway through integrin alpha6beta4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.
Bhatia
Vandanajay
V
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031, USA.
Mula
Ramanjaneya V
RV
Weigel
Nancy L
NL
Falzon
Miriam
M
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D015398:Signal Transduction
D039161:Integrin alpha6beta4; D016328:NF-kappa B; D044162:Parathyroid Hormone-Related Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D044168:Receptor, Parathyroid Hormone, Type 1; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3