Identification and Targeting of Upstream Tyrosine Kinases Mediating PI3 Kinase Activation in PTEN Deficient Prostate Cancer
Annual rept. 1 Jun 2009-31 May 2010
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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The PI3K pathway is activated by PTEN loss in most prostate cancers PCa, but the contribution of upstream RTKs that may be targeted therapeutically has not been assessed. Immunoblotting of p85 associated proteins in PTEN deficient LNCaP and C4-2 PCa cells showed a small set of tyrosine phosphorylated proteins, but they were not recognized by an anti-pYxxM motif antibody and were not found in PTEN deficient PC3 PCa cells. LCMSMS and immunoblotting showed that p85 was associated primarily with p110beta and p110delta. Basal tyrosine phosphorylation of p110beta and p110delta could be blocked by c-Src inhibitors, but this did not suppress PI3K activity, which was similarly independent of Ras. Basal PI3K activity was mediated by p110beta in PC3 cells, and by both p110beta and p110delta in LNCaP cells, while p110alpha was required for PI3K activation in response to RTK stimulation by heregulin-beta1. These findings show that basal PI3K activity in PTEN deficient PCa cells is RTK independent and can be mediated by p110beta and p110delta. Increased p110beta expression in PCa may be required for RTK independent PI3K pathway activation in adult prostate epithelium with genetic or epigenetic PTEN downregulation.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research