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Arginine Deiminase as a Novel Therapy for Prostate Cancer Induces Autophagy and Caspase-Independent Apoptosis

Departments of ¹ Biological Chemistry, ² Surgery (Division of Surgical Oncology), ³ Biophysics (Center for Biophotonics and Science Technology), ⁴ Biomedical Engineering, and ⁵ Pathology, University of California at Davis, Sacramento, California; and ⁶ Department of Molecular Microbiology and Immunology, University of Southern California Keck Medical School, Los Angeles, California

Requests for reprints: Hsing-Jien Kung, UC Davis Cancer Center, University of California - Davis Medical Center, Research III, Room 2400B, 4645 2nd Avenue, Sacramento, CA 95817. Phone: 916-734-1538; Fax: 916-734-2589; E-mail: hkung{at}ucdavis.edu and Richard J. Bold, University of California - Davis Medical Center, 4501 X Street, Sacramento, CA 95817. Phone: 916-734-5907; Fax: 916-703-5267; E-mail: richard.bold{at}ucdmc.ucdavis.edu.

Key Words: autophagy • arginine deiminase • prostate cancer

Arginine deprivation as an anticancer therapy has historically been met with limited success. The development of pegylated arginine deiminase (ADI-PEG20) has renewed interest in arginine deprivation for the treatment of some cancers. The efficacy of ADI-PEG20 is directly correlated with argininosuccinate synthetase (ASS) deficiency. CWR22Rv1 prostate cancer cells do not express ASS, the rate-limiting enzyme in arginine synthesis, and are susceptible to ADI-PEG20 in vitro. Interestingly, apoptosis by 0.3 µg/mL ADI-PEG20 occurs 96 hours posttreatment and is caspase independent. The effect of ADI-PEG20 in vivo reveals reduced tumor activity by micropositron emission tomography as well as reduced tumor growth as a monotherapy and in combination with docetaxel against CWR22Rv1 mouse xenografts. In addition, we show autophagy is induced by single amino acid depletion by ADI-PEG20. Here, autophagy is an early event that is detected within 1 to 4 hours of 0.3 µg/mL ADI-PEG20 treatment and is an initial protective response to ADI-PEG20 in CWR22Rv1 cells. Significantly, the inhibition of autophagy by chloroquine and Beclin1 siRNA knockdown enhances and accelerates ADI-PEG20–induced cell death. 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. [Cancer Res 2009;69(2):700–8]