Hong Jun, Maacha Selma, Pidkovka Nataliya, Bates Andreia, Salaria Safia N, Washington Mary K, Belkhiri Abbes
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States.
Division of Translational Medicine, Sidra Medicine, Doha, Qatar.
Front Oncol. 2022 Jul 22;12:903874. doi: 10.3389/fonc.2022.903874. eCollection 2022.
AXL receptor tyrosine kinase promotes an invasive phenotype and chemotherapy resistance in esophageal adenocarcinoma (EAC). AXL has been implicated in the regulation of autophagy, but the underlying molecular mechanism remains poorly understood. Herein, we investigate the mechanistic role of AXL in autophagy as well as metformin-induced effects on the growth and survival of EAC. We demonstrate that AXL mediates autophagic flux through activation of AMPK-ULK1 signaling in a reactive oxygen species (ROS)-dependent mechanism by glucose starvation. AXL positively regulates basal cellular ROS levels without significantly affecting mitochondrial ROS production in EAC cells. Pharmacological inhibition of cellular ROS using Trolox abrogates glucose starvation-induced AMPK signaling and autophagy. We demonstrate that AXL expression is required for metformin-induced apoptosis in EAC cells . The apoptosis induction by metformin is markedly attenuated by inhibition of autophagy through genetic silencing of Beclin1 or ATG7 autophagy mediators, thereby confirming the requirement of intact autophagy for enhancing metformin-induced apoptosis in EAC cells. Our data indicate that metformin-induced autophagy displays a pro-apoptotic function in EAC cells. We show that the metformin-induced suppression of tumor growth is highly dependent on AXL expression in a tumor xenograft mouse model of EAC. We demonstrate that AXL promotes metformin-induced apoptosis through activation of autophagy in EAC. AXL may be a valuable biomarker to identify tumors that are sensitive to metformin. Therefore, AXL expression could inform the selection of patients for future clinical trials to evaluate the therapeutic efficacy of metformin in EAC.
AXL受体酪氨酸激酶促进食管腺癌（EAC）的侵袭性表型和化疗耐药性。AXL与自噬调节有关，但其潜在的分子机制仍知之甚少。在此，我们研究AXL在自噬中的机制作用以及二甲双胍对EAC生长和存活的影响。我们证明，AXL通过葡萄糖饥饿在活性氧（ROS）依赖性机制中激活AMPK-ULK1信号传导来介导自噬通量。AXL正向调节EAC细胞中的基础细胞ROS水平，而不显著影响线粒体ROS的产生。使用托卡朋对细胞ROS进行药理学抑制可消除葡萄糖饥饿诱导的AMPK信号传导和自噬。我们证明AXL表达是二甲双胍诱导EAC细胞凋亡所必需的。通过对Beclin1或ATG7自噬介质进行基因沉默来抑制自噬，可显著减弱二甲双胍诱导的凋亡，从而证实完整的自噬是增强二甲双胍诱导EAC细胞凋亡所必需的。我们的数据表明，二甲双胍诱导的自噬在EAC细胞中具有促凋亡功能。我们表明，在EAC的肿瘤异种移植小鼠模型中，二甲双胍诱导的肿瘤生长抑制高度依赖于AXL表达。我们证明AXL通过激活EAC中的自噬促进二甲双胍诱导的凋亡。AXL可能是一种有价值的生物标志物，用于识别对二甲双胍敏感的肿瘤。因此，AXL表达可为未来评估二甲双胍在EAC中治疗效果的临床试验患者选择提供参考。
