Department of Biomedical Sciences and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
Int J Mol Sci. 2021 Jun 23;22(13):6706. doi: 10.3390/ijms22136706.
Obesity increases the risk of postmenopausal breast cancer (BC). This risk is mediated by obesity-induced changes in the adipose-derived secretome (ADS). The pathogenesis of BC in obesity is stimulated by mTOR hyperactivity. In obesity, leucine might support mTOR hyperactivity. Leucine uptake by BC cells is through L-Type Amino Acid Transporter 1 (LAT1). Our objective was to link obesity-ADS induction of LAT1 to the induction of mTOR signaling. Lean- and obese-ADS were obtained from lean and obese mice, respectively. Breast ADS was obtained from BC patients. Estrogen-receptor-positive BC cells were stimulated with ADS. LAT1 activity was determined by uptake of H-leucine. The LAT1/CD98 complex, and mTOR signaling were assayed by Western blot. The LAT1 antagonists, BCH and JPH203, were used to inhibit LAT1. Cell migration and invasion were measured by Transwell assays. The results showed obese-ADS-induced LAT1 activity by increasing transporter affinity for leucine. Consistent with this mechanism, LAT1 and CD98 expression were unchanged. Induction of mTOR by obese-ADS was inhibited by LAT1 antagonists. Breast ADS from patients with BMIs > 30 stimulated BC cell migration and invasiveness. Collectively, our findings show that obese-ADS induction of LAT1 supports mTOR hyperactivity in luminal BC cells.
肥胖增加绝经后乳腺癌（BC）的风险。这种风险是由肥胖引起的脂肪衍生分泌组（ADS）变化介导的。肥胖中 BC 的发病机制受 mTOR 过度活跃的刺激。在肥胖中，亮氨酸可能支持 mTOR 过度活跃。BC 细胞对亮氨酸的摄取是通过 L 型氨基酸转运蛋白 1（LAT1）。我们的目的是将肥胖-ADS 诱导的 LAT1 与 mTOR 信号的诱导联系起来。瘦 ADS 和胖 ADS 分别从瘦鼠和胖鼠中获得。乳腺 ADS 从 BC 患者中获得。用 ADS 刺激雌激素受体阳性 BC 细胞。通过摄取 H-亮氨酸来测定 LAT1 活性。通过 Western blot 测定 LAT1/CD98 复合物和 mTOR 信号。使用 LAT1 拮抗剂 BCH 和 JPH203 抑制 LAT1。通过 Transwell 测定法测量细胞迁移和侵袭。结果表明，肥胖 ADS 通过增加亮氨酸对转运体的亲和力来诱导 LAT1 活性。与该机制一致，LAT1 和 CD98 的表达没有变化。LAT1 拮抗剂抑制了肥胖 ADS 诱导的 mTOR。BMI 大于 30 的患者的乳腺 ADS 刺激 BC 细胞的迁移和侵袭。总之，我们的研究结果表明，肥胖 ADS 诱导的 LAT1 支持腔 BC 细胞中 mTOR 的过度活跃。
