Identification and Targeting of Upstream tyrosine Kinases Mediating PI3 Kinase Activation in PTEN Deficient Prostate Cancer

摘要

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. LC/MS/MS and immunoblotting showed that p85 was associated primarily with p110 and p110. Basal tyrosine phosphorylation of p110 and p110 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 p110 in PC3 cells, and by both p110 and p110 in LNCaP cells, while p110 was required for PI3K activation in response to RTK stimulation by heregulin-1. These findings show that basal PI3K activity in PTEN deficient PCa cells is RTK independent and can be mediated by p110 and p110. Increased p110 expression in PCa may be required for RTK independent PI3K pathway activation in adult prostate epithelium with genetic or epigenetic PTEN downregulation.