Deciphering the Role of AMPK in Doxorubicin Cardiotoxicity

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PROJECT SUMMARY/ABSTRACT Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity without compromising its antitumor efficacy would be of great clinical value. AMP-activated protein kinase (AMPK) is an essential regulator of mitochondrial homeostasis and energy metabolism that has been suggested to reduce DOX toxic effects in most cell-based studies. The anti-diabetic drug Metformin (MET) has been proposed as an agent which can attenuate DOX cardiotoxicity by activating AMPK. However, it is largely unknown whether and how AMPK per se affects DOX cardiotoxicity in vivo. Our preliminary studies confirmed the ability of MET to activate AMPK and to block the cardiotoxic effects of DOX in vitro and in vivo. Surprisingly, DOX cardiotoxicity is markedly reduced in AMPKα2 knockout (KO) mice and exacerbated by MK-8722, a potent pan-AMPK activator, suggesting that some AMPK isoforms may contribute to DOX cardiotoxicity, in stark contrast to the prevailing belief that AMPK is generally cardioprotective in the context of DOX treatment. This raises the possibility that the cardioprotective effects of MET may be mediated through mechanisms either unrelated to AMPK or related to an isoform-specific AMPK holoenzyme. This proposal will test the hypothesis that different isoforms of AMPK differentially impact DOX cardiotoxicity through distinct cellular and molecular mechanisms that regulate energy metabolism and mitochondrial quality control processes. We will ascertain the potentially differential roles of isoform-specific AMPK holoenzymes in DOX cardiotoxicity and identify the contributions of each of the eight AMPK holoenzymes expressed in cardiomyocytes using pharmacological inhibitors and activators as well as siRNA- mediated knockdown. We will also investigate whether modulating AMPK activity affects DOX cardiotoxicity through its effects on mitochondrial fission or mitophagy. Given the emerging importance of each of the isoforms in AMPK function, tremendous effort has been made to develop agents that can modulate AMPK activity in an isoform-specific manner. The proposed study is expected to generate new knowledge that will shed light on the functional role of each of the AMPK isoforms in DOX cardiotoxicity, suggesting novel isoform- selective therapeutics. This project will have a positive impact on the treatment of many types of cancer that are sensitive to DOX.