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


METHODS
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.


RESULTS
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 (P = 0.01) reduced arginase II activity and suppressed cell growth in cells exhibiting high arginase activity.The depletion of L-arginine by mRCC induced the decrease expression of CD3zeta a key element for T-cell function.


CONCLUSIONS
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 CD3zeta. 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.
Tate
David J
DJ
Stanley S, Scott Cancer Center, LSUHSC, New Orleans, USA. dtate1@lsuhsc.edu
Vonderhaar
Derek J
DJ
Caldas
Yupanqui A
YA
Metoyer
Toye
T
Patterson
John R
JR
Aviles
Diego H
DH
Zea
Arnold H
AH
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C404735:N(omega)-hydroxynorarginine; D001120:Arginine; D001119:Arginase