Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy
Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy
复制标题
靶向 AMPK 信号通路克服癌症治疗的耐药性
DOI：
10.2174/1389450116666150316223655
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发表时间：
2016-01-01
影响因子：
3.2
通讯作者：
Lin, Yi
中科院分区：
文献类型：
--
作者：
Wang, Zhiyu;Liu, Pengxi;Lin, Yi
多药耐药（MDR）是限制癌症化学疗法或放射疗法疗效的关键因素之一。越来越多的证据表明，多药耐药是一个由多种因素调控的复杂过程，其中应激反应分子被认为起着核心作用。腺苷酸活化蛋白激酶（AMPK）是平衡能量供应的主要调节因子，它通过协调多种代谢途径，最终保护细胞免受有害应激。值得注意的是，最近研究表明，AMPK的激活可介导耐药癌细胞的代谢重编程，包括促进瓦尔堡效应和线粒体生物合成。此外，AMPK的活性还被证明可调节癌症干细胞的自我更新能力，而癌症干细胞往往对化疗具有抗性。另外，AMPK的磷酸化在介导自噬诱导过程中至关重要，自噬是一种通过在应激条件下降解细胞成分以满足营养需求，从而有效调节化疗敏感性的过程。与此同时，以AMPK为靶点的药物研发工作已经展开，以验证AMPK在癌症预防和治疗中的病理学意义。尽管针对AMPK调节用于癌症治疗的相关证据存在争议，但这可能归因于特定组织中AMPK亚型的差异、脱靶效应、药物给药的程度和持续时间以及应激条件的实验设置不同。本综述将聚焦于AMPK介导的癌症治疗耐药性，并探讨其潜在的治疗意义以及靶向药物的开发。
Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development.