TY - JOUR
T1 - Parathyroid hormone-related protein regulates cell survival pathways via integrin α6β4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling
AU - Bhatia, Vandanajay
AU - Mula, Ramanjaneya V.
AU - Weigel, Nancy L.
AU - Falzon, Miriam
PY - 2009/7
Y1 - 2009/7
N2 - 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 α6β 4 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-3as 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-3cells. 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-3and 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-κB activity via a PI3K-dependent pathway. Integrin α6β4 is known to activate PI3K. Here, we also show that knockdown of integrin α6β4 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 α6β4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.
AB - 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 α6β 4 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-3as 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-3cells. 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-3and 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-κB activity via a PI3K-dependent pathway. Integrin α6β4 is known to activate PI3K. Here, we also show that knockdown of integrin α6β4 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 α6β4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.
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U2 - 10.1158/1541-7786.MCR-08-0568
DO - 10.1158/1541-7786.MCR-08-0568
M3 - Article
C2 - 19584267
AN - SCOPUS:67651149656
SN - 1541-7786
VL - 7
SP - 1119
EP - 1131
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 7
ER -