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) : MacKeigan, Jeffrey P


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a570540.pdf


Report Date : Jan 2013


Pagination or Media Count : 72


Abstract : Phosphatidylinositol-3-phosphate (PI(3)P) is concentrated on endocytic and autophagic vesicles and recruits effector proteins critical for these processes. In an effort to understand the phosphatase regulation of PI(3)P, we performed an RNA interference (RNAi) screen and found that knockdown of PTPRS (PTPsigma), a dual-domain protein tyrosine phosphatase (PTP), increases cellular PI(3)P and hyperactivates both constitutive and induced autophagy. We have found that PTPsigma localizes to PI(3)P-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 PI(3)P 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.


Descriptors :   *PROSTATE CANCER , CULTURE , LIPIDS , PHOSPHATASES , SIGNALS


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE