Targeting ferroptosis in cancer therapy

Project Summary Studying regulated cell death is critical for our understanding of tumor suppression and development of novel effective cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death that is induced by excessive lipid peroxidation, is morphologically and mechanistically distinct from other forms of regulated cell death such as apoptosis. However, in contrast to our deep understanding of apoptosis, how ferroptosis is regulated and coordinates with other cellular signaling in tumor suppression remains much less well understood. There also exists a significant need to translate our understanding of ferroptosis mechanisms into effective cancer therapies. Our long-term goal is to understand the mechanism(s) of action of anti-neoplastic agents and/or combinations of agents that target ferroptosis in cancer therapy. The objective of this application is to determine the role and mechanisms of AMP-activated protein kinase (AMPK), a critical sensor of cellular energy status, in regulating ferroptosis and the relevance of these regulatory functions to tumor suppression and treatment. Energy stress depletes ATP and induces cell death. Surprisingly, our recent study revealed that energy stress can potently suppress ferroptotic cell death through activating AMPK. Cancer cells with high basal AMPK activation are resistant to ferroptosis, and AMPK inactivation sensitizes such cancer cells to ferroptosis. Our recent publication and new preliminary data support the central hypothesis that AMPK inhibits ferroptosis through AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and biosynthesis of polyunsaturated fatty acid (PUFA) as well as other unidentified downstream effectors. AMPK can have either tumor-suppressive or -promoting functions, depending on the context. We further hypothesize that AMPK’s tumor-promoting function is at least partly mediated by its inhibition of ferroptosis, and combining AMPK inhibitors and ferroptosis inducers (FINs) is a novel therapeutic strategy for treating AMPK-dependent cancers. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1: To study the mechanisms by which AMPK inhibits ferroptosis in cancer cells. Specific Aim 2: To determine the relevance of ferroptosis to AMPK-mediated tumor development and treatment. It is expected that our proposed studies will clarify how AMPK regulates PUFA biosynthesis, identify novel regulatory mechanisms of ferroptosis pathways, and reveal a previously unrecognized function of ferroptosis suppression in AMPK-mediated tumor promotion in cancer. Our proposal is highly innovative because it focuses on a previously unexplored pathway linking AMPK regulation of ferroptosis to tumor development. Our proposed studies will have significant impact on both our basic understanding of ferroptosis and our ability to target AMPK or ferroptosis in cancer treatment.