The Role of Autophagy with Arginine Deiminase as a Novel Prostate Cancer Therapy
Annual summary rept. 1 Jul 2008-30 Jun 2009
CALIFORNIA UNIV DAVIS
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Arginine deprivation by arginine deiminase ADI is a novel therapy that is effective against prostate cancers that lack argininosuccinate synthetase ASS, the rate-limiting enzyme for de novo arginine synthesis. We show that in ASS negative CWR22Rv1 prostate cancer cells, ADI rapidly induced autophagy through AMPKmTORS6K as well as ERK12 pathways in order to delay the onset of caspase-independent apoptosis. Inhibiting autophagy with chloroquine or Beclin1 siRNA accelerated and enhanced ADI-induced apoptosis. PC3 cells, which express reduced ASS, also undergo autophagy and are responsive to autophagy inhibition and ADI-PEG20 treatment. In contrast, LNCaP cells highly express ASS and are therefore resistant to both ADI-PEG20 and autophagic inhibition. These data point to an interrelationship among ASS deficiency, autophagy, and cell death by ADI-PEG20. Finally, a tissue microarray of 88 prostate tumor samples lacked expression of ASS, indicating ADI-PEG20 is a potential novel therapy for the treatment of prostate cancer.
- Medicine and Medical Research