Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma

• Main Authors: Patterson John R, Metoyer Toye, Caldas Yupanqui A, Vonderhaar Derek J, Tate David J, Aviles Diego H, Zea Arnold H
• Format: Article
• Language: English
• Published: BMC 2008-09-01
• Series: Journal of Hematology & Oncology
• Online Access: http://www.jhoonline.org/content/1/1/14

<p>Abstract</p> <p>Background</p> <p>L-arginine is the common substrate for the two isoforms of arginase. Arginase I, highly expressed in the liver and arginase II mainly expressed in the kidney. Arginase I-producing myeloid derived suppressor cells have been shown to inhibit T-cell function by the depletion of L-arginine. On the other hand, arginase II has been detected in patients with cancer and is thought to metabolize L-arginine to L-ornithine needed to sustain rapid tumor growth; however its role in L-arginine depletion is unclear. Thus, in tumor biology, L-arginine metabolism may play a dual role in tumor growth and in the induction of T cell dysfunction. Therefore, we studied in murine renal cell carcinoma (RCC) cell lines, the effect of arginase II on tumor cell proliferation and L-arginine depletion. The effect of arginase inhibitors on cell proliferation was also tested.</p> <p>Methods</p> <p>Three murine renal cell carcinoma (mRCC) cell lines were tested for the presence of arginase. nor-NOHA, an arginase inhibitor was used to substantiate the effect of arginase on cell growth and L-arginine depletion. Amino acid levels were tested by HPLC.</p> <p>Results</p> <p>Our results show that mRCC cell lines express only arginase II and were able to deplete L-arginine from the medium. Cell growth was independent of the amount of arginase activity expressed by the cells. nor-NOHA significantly (<it>P </it>= 0.01) reduced arginase II activity and suppressed cell growth in cells exhibiting high arginase activity.</p> <p>The depletion of L-arginine by mRCC induced the decrease expression of CD3ζ a key element for T-cell function.</p> <p>Conclusion</p> <p>The results of this study show for the first time that arginase II produced by RCC cell lines depletes L-arginine resulting in decreased expression of CD3ζ. These results indicate that RCC cell lines expressing arginase II can modulate the L-arginine metabolic pathway to regulate both cell growth and T-cell function. Blocking arginase may lead to a decrease in RCC cell growth and aid in restoring immune function by increasing L-arginine availability for T-cell use. Understanding the interplay between arginase II and its interaction with the immune system may provide future therapeutic benefits to treat patients with RCC.</p>