Accession Number:

ADA570540

Title:

Autophagy Signaling in Prostate Cancer: Identification of a Novel Phosphatase

Descriptive Note:

Final rept. 23 Jul 2009-22 Jan 2013

Corporate Author:

VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI

Personal Author(s):

Report Date:

2013-01-01

Pagination or Media Count:

72.0

Abstract:

Phosphatidylinositol-3-phosphate PI3P is concentrated on endocytic and autophagic vesicles and recruits effector proteins critical for these processes. In an effort to understand the phosphatase regulation of PI3P, we performed an RNA interference RNAi screen and found that knockdown of PTPRS PTPsigma, a dual-domain protein tyrosine phosphatase PTP, increases cellular PI3P and hyperactivates both constitutive and induced autophagy. We have found that PTPsigma localizes to PI3P-positive membranes in cells and its vesicular localization is enhanced during autophagy. Furthermore, PTPsigma is proteolytically processed from its location at the cell surface into a membrane-bound C-terminal fragment, which appears to be targeted to the lysosome. Taken together, our findings propose a novel role for PTPsigma and provide insight into the regulation of PI3P and autophagy. Intriguingly, we have previously demonstrated that RNAi-mediated knockdown of PTPsigma confers chemoresistance to cancer cells in culture. In addition, reduced expression of PTPsigma was found during the progression from primary prostate cancer to metastatic disease. Accordingly, our central hypothesis is that autophagy is activated in the absence of PTPsigma as a mechanism of chemoresistance, thereby densensitizing prostate cancer cells to chemotherapeutic stress and supporting disease progression.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE