AMPK 为细胞能量感受器，在肿瘤发生中的作用已成为当前肿瘤生物学的研究重点。肿瘤细胞的代谢特点是其能量主要来源于糖酵解，即使在有氧条件下，这一途径也占优势，该现象称为Warburg效应，被认为是肿瘤治疗的新靶点。仅少数几篇文献报道AMPK对Warburg效应的调节作用，但结论相反。我们的前期工作发现AMPK定位于细胞的线粒体，将AMPK的活性突变体靶向定位于肺癌细胞A549的线粒体能抑制糖酵解，刺激脂肪酸氧化，抑制细胞生长和异体移植肿瘤形成。因此，我们的初步结果支持AMPK对Warburg效应的抑制作用。本课题将进一步探索AMPK向线粒体迁移的生理、病理和药理学条件，研究AMPK与线粒体结合对细胞能量代谢和线粒体功能的影响，寻找AMPK在线粒体的作用位点和靶分子，确立AMPK线粒体定位对肿瘤发生发展的抑制作用。该研究课题有助于澄清关于AMPK对Warburg效应作用的争议。

AMP-activated protein kinase (AMPK) is a cellular fuel sensor that is activated under stress, leading to suppression of ATP- consuming anabolic processes and stimulation of catabolism and ATP generation. AMPK is currently a research focus of cancer biology. The metabolism of cancer cells is featured by glycolysis, a major energy generating mechanism even under aerobic circumstances. This phenomenon is called Warburg effect, which is nowadays regarded a therapeutic target for cancer. Only a few papers described the regulation of Warburg effect by AMPK, with opposing effects. Our preliminary data showed that AMPK was localized to mitochondria. We employed genetic engineering to target an active variant of AMPK to mitochondria and found that this AMPK variant inhibited glycolysis, stimulated mitochondrial fatty acid oxidation, and attenuated the growth of cancer cells in vitro and Xenograft tumor in vivo. Collectively, our data support a negative effect of AMPK on Warburg phenomenon. Therefore, in this grant application, we aim to carry out the studies in depth and width. We will (1) explore the physiological, pathological and pharmacological conditions for AMPK to migrate to mitochondria, (2) assess the effects of AMPK localization to mitochondria on cellular energy metabolism and mitochondrial function, (3) identify steps and partners/targets of AMPK action on mitochondrial respiratory chain and (4), determine the inhibitory effect of mitochondrial AMPK on tumorigenesis and tumor progression. Altogether, our studies would consolidate our argument that AMPK serves as a metabolic tumor suppressor and help to clarify the controversial role of AMPK in Warburg effect. In addition, since metformin, a pharmacological activator of AMPK, is being used for clinical trials of various cancers, the completion of our studies will provide guide and strategy for these trials and present new targets for cancer therapy.