Targeting amino acid transport to block mTORC1 and cell cycle in prostate cancer

Background: Amino acids such as leucine and glutamine are important for tumor cell growth, mTORC1 activation, cell cycle and cellular metabolism. As such, amino acid transporters such as LAT1, LAT3 and ASCT2 are commonly upregulated in a variety of cancers1-3. The amino acid transporter ASCT2 (SLC1A5) mediates uptake of glutamine in cancer cells, working together with leucine transporters such as LAT1 and LAT3. We have recently reported that ASCT2 and LAT1 are significantly upregulated in melanoma, and that ASCT2 inhibition significantly decreases glutamine uptake, cell growth, cell cycle and mTORC1 pathway activation1. Furthermore, we have previously shown that both LAT3 and ASCT2 expression are regulated by the androgen receptor in prostate cancer2,3. In this current study we further examine ASCT2 expression levels in prostate cancer, and target ASCT2-mediated glutamine uptake in order to inhibit mTORC1 pathway, metabolism and cell growth.

Results: We have used immunohistochemistry on prostate cancer tissue microarrays to show that ASCT2 protein is highly expressed in primary prostate cancer. Interestingly, levels decreased after neoadjuvant hormone therapy, before returning to pretreatment levels in recurrent disease. Blocking ASCT2 function using the amino acid analogue benzylserine led to a significant reduction in glutamine uptake, metabolism (oxygen consumption rate, glutamine oxidation and lipogenesis), cell cycle progression, mTORC1 pathway activation and cell growth. Furthermore, shRNA-mediated ASCT2 knockdown in vitro and in vivo (PC-3 prostate cancer cell xenografts) led to a significant reduction in cell/tumor growth.

Conclusions: Amino acid uptake mediated by ASCT2 is essential for multiple cancer cell pathways including mTORC1 signaling and metabolism. As such, ASCT2 targeted therapies are an effective means of inhibiting cellular energy, protein synthesis and cell growth in prostate cancer.