Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer

Abstract

Despite the known importance of androgen receptor (AR) signaling in prostate cancer (PCa), the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in PCa cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in PCa. Correspondingly, gene expression signatures of AR activity correlated with SLC1A4 and SLC1A5 mRNA levels in clinical cohorts. Interestingly, MYC, a canonical oncogene in PCa and previously described master regulator of glutamine metabolism, was only a context-dependent regulator of SLC1A4 and SLC1A5 levels, being unable to regulate either transporter in phosphatase and tensin homolog (PTEN) wild-type cells. In contrast, rapamycin was able to decrease the androgen-mediated expression of SLC1A4 and SLC1A5 independent of PTEN status, indicating that mechanistic target of rapamycin complex 1 (mTORC1) was needed for maximal AR-mediated glutamine uptake and PCa cell growth. Taken together, these data indicate that three well-established oncogenic drivers (AR, MYC and mTOR) function by converging to collectively increase the expression of glutamine transporters, thereby promoting glutamine uptake and subsequent prostate cancer cell growth. Implications: AR, MYC and mTOR converge to increase glutamine uptake and metabolism in prostate cancer through increasing the levels of glutamine transporters.

Mitochondrial General Control of Amino Acid Synthesis 5 Like 1 Regulates Glutaminolysis, Mammalian Target of Rapamycin Complex 1 Activity, and Murine Liver Regeneration

“…At the same time, given that mTORC1 activation targets Slc1a5 transcription, we hypothesized that a positive feedback loop of transcriptional activation of Slc1a5 was through GCN5L1‐depletion–mediated glutaminolysis. However, induction of Slc1a5 transcript levels in response to GCN5L1 depletion may be an alternate or parallel mechanism to induce glutamine uptake, GLS2 activation, glutaminolysis, and mTORC1 signaling.…”

“…At the same time, given that mTORC1 activation targets Slc1a5 transcription, (27) we hypothesized that a positive feedback loop of transcriptional activation of Slc1a5 was through GCN5L1-depletionmediated glutaminolysis. However, induction of Slc1a5 .…”

The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation

“…Although it has been reported some channel proteins and metabolic enzymes including IDH1, IDH2, BCAT1, OGDH, GDH, SLC1A4, SLC1A5, GLUL, and GLA were involved in the metabolism of α-ketoglutarate in many cell types [9,[23][24][25][26][27][28][29][30][31], the mechanism of intracellular α-ketoglutarate regulation during HSC activation has not been previously reported. The main metabolic sources of intracellular α-ketoglutarate including glucose and glutamine were kept sufficient in the cell culture medium in our research [32,33], while the expression of channel proteins and metabolic enzymes mentioned above were investigated during HSC activation.…”

Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?

“…Under normal conditions, glucose is metabolized to pyruvate by a series of enzymatic steps in the glycolytic pathway, which is subsequently oxidized by the TCA and respiratory chain, generating CO 2 , H 2 O, and 32 or 34 molecules of ATP per glucose molecule, while in glycolysis, 2 ATPs/glucose are produced. This alteration in glucose metabolism depends on increased transcription of GLUTs, glycolytic enzymes, and oncogenes and increased demand of mitochondrial metabolism for biosynthetic processes [4][5][6].…”