Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

Abstract

Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitize resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signaling, prevents this Warburg shift. Regulating glucose transporter and pro-apoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest intermittent fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage, and possibly even early-stage, HCC.

Complementary Omics Strategies to Dissect p53 Signaling Networks Under Nutrient Stress

“…Recent reports showed that p53 protein abundance is increased in cultured hepatocytes by starvation [28] and that p53 signaling is necessary for the physiological response to fasting in the mouse liver [28,30]. Furthermore, our most recent data provide evidence for the requirement of p53 for the effects of fasting in enhancing hepatocellular carcinoma therapy (Preprint at BioRxiv [29]). Thus, our ndings add to a ourish of recent reports that establish p53 as central and potent metabolic regulator in transformed as well as in nontransformed cells [49,65].…”

“…and that p53 is necessary and su cient for the therapy-enhancing effect of fasting on sorafenib treatment of hepatocellular carcinoma (Preprint at BioRxiv [29]). Moreover, hepatic p53 was recently shown to be stabilized by O-GlcNAcylation in fasted mice, which was shown to be essential for the regulation of gluconeogenesis in the liver [30].…”

Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis

“…HepG2 cells (ATCC) were cultivated in Dulbecco’s modified Eagle’s medium with 25 mM of glucose, supplemented with 4 mM glutamine, 10% FBS, and 500 U/ml penicillin-streptomycin (GIBCO) as previously ( 52 ). Glycogen was quantified using a kit (K646-100, BioVision).…”

Combination of Ashwagandha Water Extract and Intermittent Fasting as a Therapy to Overcome Cisplatin Resistance in Breast Cancer: An in vitro and in vivo Study

“…Nevertheless, IF can reverse MDR by several pathways as revealed in the literature. The first way is by increasing p53, which is substantial for sensitization (47). By the same token, IF suppresses IGF-1 and IGF-1 receptors and that increases sensitivity to chemotherapy (48) The safety profile of anticancer agents is crucial to evaluating their toxicity.…”