Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer

Abstract

Background Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC. Methods The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry. Results SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02). Conclusions These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.

Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis

“…We also monitored the expression of two other members in the SLC38 family, namely SLC38A1 and SLC38A2, both of which accept glutamine as a substrate. Two recent studies have reported that SLC38A2 plays a critical role in supplying glutamine to breast cancer cells [16,17]. But, we did not find any difference in the expression of these two transporters between non-malignant and TNBC cell lines (Fig.…”

Effect of Heat Stress on Bovine Mammary Cellular Metabolites and Gene Transcription Related to Amino Acid Metabolism, Amino Acid Transportation and Mammalian Target of Rapamycin (mTOR) Signaling

“…A similar decrease in the gene expression of SLC38A2 induced by HS in the breast muscle of broilers was observed [ 35 ]. Moreover, the lower expression of SLC38A2 was observed to decrease glutamicacid (Gln) consumption and inhibit cell growth [ 63 ]. Combined with the observation that HS led to higher Gln and Glu intracellular concentration in the HS group in the present work, it is plausible that the decrease in the gene expression of SLC38A2 might be one of the regulated ways for reducing the Glu and Gln consumption to adapt to HS in BMECs.…”

Regulation of mTORC1 activity by the Golgi apparatus

“…In addition, the Ser/Thr protein kinase, STK25, a Golgi-localised kinase that regulates Golgi morphology and interacts with GOLPH3, downregulates mTORC1 activity and suppresses cell proliferation 44 . Members of the SLC38 amino acid transporters, namely SNAT2 and SNAT10, are Golgi-localised under certain conditions and have been reported to influence mTORC1 activity 45 – 47 . However, the intracellular location of mTORC1 activation via these transporters is not clear.…”