Deprivation of arginine by recombinant human arginase in prostate cancer cells

Journal of Hematology & Oncology

Chung-Tsen Hsueh¹  Paul Ning-Man Cheng³  Yun-Chung Leung²  Wai-Hung Lo²  Stephanie M Knebel⁴  Eddy C Hsueh⁴ 

[1] Division of Medical Oncology and Hematology, Loma Linda University, Loma Linda, CA, 92354, USA;Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China;Bio-Cancer Treatments International Ltd., Hong Kong Science Park, Bio-informatics Building, Hong Kong, China;Department of Surgery, Saint Louis University, St. Louis, MO, USA

关键词: Autophagy;    Mammalian target of rapamycin;    Argininosuccinate synthetase;    Ornithine carbamoyl transferase;    Prostate cancer;    Arginase;   

Others  :  822506
DOI  :  10.1186/1756-8722-5-17

 received in 2012-03-28, accepted in 2012-04-30,  发布年份 2012

【 摘 要 】

Background

Recombinant human arginase (rhArg) has been developed for arginine deprivation therapy in cancer, and is currently under clinical investigation. During pre-clinical evaluation, rhArg has exhibited significant anti-proliferative activity in cancer cells deficient in the expression of ornithine carbamoyl transferase (OCT). Interestingly, a variety of cancer cells such as melanoma and prostate cancer deficient in argininosuccinate synthetase (ASS) are sensitive to arginine deprivation by arginine deiminase. In this study, we investigated levels of gene expression of OCT and ASS, and the effects of rhArg in human prostate cancer cells: LNCaP (androgen-dependent), PC-3 and DU-145 (both androgen-independent).

Results

Quantitative real-time PCR showed minimal to absent gene expression of OCT, but ample expression of ASS expression in all 3 cell lines. Cell viability assay after 72-h exposure of rhArg showed all 3 lines had half maximal inhibitory concentration less than or equal to 0.02 U/ml. Addition of ornithine to cell culture media failed to rescue these cells from rhArg-mediated cytotoxicity.

Decreased phosphorylation of 4E-BP1, a downstream effector of mammalian target of rapamycin (mTOR), was noted in DU-145 and PC-3 after exposure to rhArg. Moreover, there was no significant apoptosis induction after arginine deprivation by rhArg in all 3 prostate cancer cell lines.

Conclusion

rhArg causes significant cytotoxicity in LNCaP, DU-145 and PC-3 prostate cancer cells which all demonstrate decreased OCT expression. Inhibition of mTOR manifested by hypophosphorylation of 4E-BP1 suggests autophagy is involved as alternative cell death mechanism. rhArg demonstrates a promising novel agent for prostate cancer treatment.

【 授权许可】

   
2012 Hsueh et al.; licensee BioMed Central Ltd.

【 图 表 】

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