The Role of Autophagy with Arginine Deiminase as a Novel Prostate Cancer Therapy
Abstract
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 AMPK/mTOR/S6K as well as ERK1/2 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2009
- Accession Number
- ADA510982
Entities
People
- Randle Kim
Organizations
- University of California