Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis.
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 microg/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 microg/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
Kim
Randie H
RH
Department of Biological Chemistry, Division of Surgical Oncology, Center for Biophotonics and Science Technology, University of California at Davis, Sacramento, California 95817, USA.
Coates
Jodi M
JM
Bowles
Tawnya L
TL
McNerney
Gregory P
GP
Sutcliffe
Julie
J
Jung
Jae U
JU
Gandour-Edwards
Regina
R
Chuang
Frank Y S
FY
Bold
Richard J
RJ
Kung
Hsing-Jien
HJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001124:Argininosuccinate Synthase / Q000096:biosynthesis / Q000172:deficiency; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D043823:Taxoids; D000077143:Docetaxel; D011092:Polyethylene Glycols; D006867:Hydrolases; D053148:Caspase 3; C512527:ADI PEG20; C019723:arginine deiminase; D001124:Argininosuccinate Synthase