Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis

Randie H. Kim, Jodi M. Coates, Tawnya L. Bowles, Gregory P. McNerney, Julie Sutcliffe, Jae U. Jung, Regina Gandour-Edwards, Frank Y S Chuang, Richard J. Bold, Hsing Jien Kung

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

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 Mg/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.

Original languageEnglish
Pages (from-to)700-708
Number of pages9
JournalCancer Research
Volume69
Issue number2
DOIs
Publication statusPublished - Jan 15 2009
Externally publishedYes

Fingerprint

Autophagy
Caspases
Prostatic Neoplasms
Apoptosis
Argininosuccinate Synthase
Therapeutics
Citrullinemia
Arginine
docetaxel
arginine deiminase
ADI PEG20
Neoplasms
Cell Death
Chloroquine
Heterografts
Small Interfering RNA
Prostate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. / Kim, Randie H.; Coates, Jodi M.; Bowles, Tawnya L.; McNerney, Gregory P.; Sutcliffe, Julie; Jung, Jae U.; Gandour-Edwards, Regina; Chuang, Frank Y S; Bold, Richard J.; Kung, Hsing Jien.

In: Cancer Research, Vol. 69, No. 2, 15.01.2009, p. 700-708.

Research output: Contribution to journalArticle

Kim, RH, Coates, JM, Bowles, TL, McNerney, GP, Sutcliffe, J, Jung, JU, Gandour-Edwards, R, Chuang, FYS, Bold, RJ & Kung, HJ 2009, 'Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis', Cancer Research, vol. 69, no. 2, pp. 700-708. https://doi.org/10.1158/0008-5472.CAN-08-3157
Kim, Randie H. ; Coates, Jodi M. ; Bowles, Tawnya L. ; McNerney, Gregory P. ; Sutcliffe, Julie ; Jung, Jae U. ; Gandour-Edwards, Regina ; Chuang, Frank Y S ; Bold, Richard J. ; Kung, Hsing Jien. / Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. In: Cancer Research. 2009 ; Vol. 69, No. 2. pp. 700-708.
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AU - Sutcliffe, Julie

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