Exploring the Role of Caveolin1 Upregulation in the Prostate
Caveolin1 (CAV1) is a multi-functional protein with dual function in terms of malignant growth. Cav1 is consistently found upregulated in prostate cancer models and serves as a marker for poor prognosis. In prostate cancer cell lines, CAV1 was found to positively regulate androgen receptor transcriptional activity but the significance of these findings in vivo were unclear. To determine the role of Cav1 in androgen receptor signaling, a mouse model of overexpression was utilized and subjected to castration and subsequent testosterone supplementation. This work demonstrated that Cav1 overexpression led to an increase in androgen-dependent prostate growth and proliferation in the murine prostate. While there was no change in levels of total androgen receptor, there was a significant increase in an Akt-mediated phosphorylation site, serine 210. The mice also displayed an increase in ribosomal S6 protein, a downstream component of the mTOR pathway. To determine the effects that CAV1 overexpression had on proliferation in human prostate cancer, CAV1 was stably overexpressed in androgen dependent LNCaP cells. CAV1 led to an increase in proliferation and proliferative markers including phosphorylated retinoblastoma protein, and histone H3. These cells also exhibited increased invasion, although no change in migration was observed. Similar to our mice, these cells displayed increased activation of the mTOR pathway. Importantly, CAV1 and mTOR were found in a complex together, and the proliferative and invasive advantage of the CAV1 cells was inhibited by the use of the mTOR inhibitor rapamycin. Taken together, this work provides evidence that Cav1 is a positive regulator of prostate cell proliferation and may serve as a biomarker for patients likely to respond to inhibitors of the mTOR pathway.
Bryant, Kelly, "Exploring the Role of Caveolin1 Upregulation in the Prostate" (2013). ETD Collection for Thomas Jefferson University. AAI3556380.