Metabolic Regulation of Ferroptosis, Nutrient Dependency, and Tumor Suppression
Our lab has a long-standing interest in understanding nutrient signaling and metabolic stress response in both normal and cancer cells. We are interested in the questions: 1) how normal/cancer/stem cells sense nutrient availability? 2) how cancer cell adapt to survive and grow under metabolic stress or nutrient deprivation? and 3) how to target metabolic vulnerabilities in cancer treatment? Our previous studies focused on the role of FoxO/TSC/LKB1 tumor suppressor network in energy sensing, cancer metabolism, and stem cell maintenance. These studies have delineated an intimate link between tumor suppressor pathways that control energy sensing/metabolism and those that regulate stem cell homeostasis (Gan et al, PNAS, 2008; Gan et al, Cancer Cell, 2010; Gan et al, Nature, 2010), and identified novel mechanisms on how cancer cells adapt to metabolic stress or cancer therapy (Lin et al, 2014, Cancer Research; Liu et al, Nature Cell Biology, 2016; Xiao et al, Nature Communications, 2017; Dai et al, PNAS, 2017). Our current research focuses on two related research topics that have emerged from our more recent work: 1) the role and mechanisms of ferroptosis in cellular metabolism, tumor suppression, and cancer therapy, and 2) cystine metabolism-induced nutrient dependency and its implication in cancer therapy
1. Ferroptosis in cellular metabolism, tumor suppression, and cancer therapy
Ferroptosis is a form of regulated cell death that is triggered by iron-dependent lipid peroxidation with distinctive features and underlying mechanisms from other forms of regulated cell death such as apoptosis. Cells have evolved elegant defense mechanisms to suppress ferroptosis, prominent among which is the SLC7A11-GPX4 signaling axis, wherein amino acid transporter SLC7A11 imports cystine to generate cysteine for glutathione (GSH) synthesis and GPX4 (a glutathione peroxidase) subsequently uses GSH to detoxify lipid peroxides and inhibit ferroptosis (Fig. 1). Consequently, cystine starvation or inactivation of GPX4 or SLC7A11 triggers potent ferroptosis in many cancer cells.
In recent years, our research has delved into understanding ferroptosis in tumor biology while we were studying tumor suppressive mechanisms of tumor suppressor BAP1, a H2A deubiquitinase. Through comprehensive analyses of BAP1-target genes in cancer cells, we identified cystine transporter SLC7A11 as a key BAP1 target gene in tumor suppression and revealed a BAP1-mediated epigenetic mechanism that links ferroptosis to tumor suppression (Zhang et al, Nature Cell Biology, 2018). Our subsequent study also uncovered a critical role of ferroptosis in radiotherapy-induced cell death and tumor suppression and suggested to combine radiotherapy and ferroptosis inducers in cancer treatment (Lei et al, Cell Research, 2020). Our findings together reveal that ferroptosis is an important tumor suppression mechanism and provide a broad framework for further understanding and targeting ferroptosis in cancer therapy. Currently, we are employing multi-disciplinary approaches, including sophisticated genetic mouse models, clinical investigation, and functional studies to further dissect the role and mechanisms of ferroptosis in tumor suppression and to therapeutically target ferroptosis in cancer treatment.
Considering that ferroptosis is inherently linked to metabolic stress (such as cystine deprivation, reactive oxygen species, and iron overload), we have also been studying the interplay between cellular metabolism and ferroptosis. In one project, we investigated the role of energy stress in ferroptosis regulation. While it is well known that energy stress depletes ATP and induces cell death, we recently showed that energy stress potently suppresses ferroptosis by activating the energy sensor AMPK. Functional and lipidomic analyses revealed that AMPK inhibits ferroptosis through phosphorylating acetyl-CoA carboxylase and suppressing polyunsaturated fatty acid biosynthesis. This study therefore reveals an unexpected coupling between ferroptosis and AMPK-mediated energy sensing signaling (Lee et al, Nature Cell Biology, 2020). Currently, we are applying integrated approaches, including metabolomic, lipidomic, and proteomic analyses and CRISPR screens, to gain deeper mechanistic understanding of ferroptosis and its interplay with cellular metabolism.
2. Cystine metabolism-induced nutrient dependency and its
implication in cancer therapy
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and protecting cells from ferroptosis, and SLC7A11 is frequently overexpressed in cancers. We recently made unexpected findings that this metabolic reprogramming also comes at a significant cost for SLC7A11-high cancer cells: constitutively reducing cystine to cysteine presents a substantial drain on the cellular NADPH pool and renders such cells highly dependent on pentose phosphate pathway (PPP) and glucose for survival (Fig. 2A). Limiting glucose supply to SLC7A11-high cancer cells results in disulfide stress and rapid cell death (Fig. 2B). Our subsequent preclinical studies validated the concept to target this metabolic vulnerability in SLC7A11-high cancers (Liu et al, Nature Cell Biology, 2020). Recently we also showed that glucose starvation-induced NADPH depletion in SLC7A11-high cancer cells can trigger signaling events to decrease H2A ubiquitination and activate ER stress gene expression to mediate subsequent cell death (Zhang et al, Cancer Research, 2020).
Our future plan in this project includes: 1) to therapeutically target SLC7A11-induced nutrient dependency and disulfide stress in SLC7A11-high cancers, such as BAP1-mutant renal cancer and KEAP1-mutant lung cancer; 2) to further study SLC7A11-induced cell death under other metabolic stress conditions; 3) to employ CRISPR screens and other approaches to understand the nature and dissect the mechanisms of SLC7A11-induced cell death under glucose starvation; and 4) to study disulfide stress-initiated cellular signaling in SLC7A11-high cancer cells by conducting redox proteomic analyses.