A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis

Abstract

Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein ( HILPDA ). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.

Hypoxia inducible factor-2α increases sensitivity of colon cancer cells towards oxidative cell death

“…4B) either alone or in combination with FG4592. This data is consistent with a recent work, that suggest that HIF-2α-dependent lipid alterations increase ferroptotic cell death in renal cancer derived cell lines 31 . We analyzed the expression of two lipid genes important in ferroptosis sensitization in renal cancers, hypoxia inducible lipid droplet associated protein (HILPDA) and perilipin 2 (PLIN2).…”

“…We also observe the similar effect in a panel of CRC cell lines, where either the growth inhibition or lipid ROS production by erastin or RSL3 was significantly increased by pre-treating the cells with a hypoxia mimetic. In a recent study HIF-2α has been shown to be driving vulnerability to RSL3-induced ferroptosis in clear-cell renal cell carcinoma (ccRCC) 31 . Our results also show a similar mechanism in colon cancer cells, where HIF-2α deficient CRC cells are completely resistant to high concentrations of erastin or RSL3.…”

“…Ferroptosis is characterized by the loss of lipid peroxide repair capacity by the phospholipid glutathione peroxidase GPX4, the availability of redox-active iron, and oxidation of polyunsaturated fatty acid (PUFA)containing phospholipids 29,30 . Ferroptotic death is associated with various pathological conditions, including hepatocellular degeneration, acute kidney injury, hemochromatosis, traumatic brain injury, and neurodegeneration 31,32 . Recently ferroptotic cell death emerged as a potent tool to target drug-tolerant persisted cancer cells 33,34,35 .…”

GOT1 Inhibition Primes Pancreatic Cancer for Ferroptosis through the Autophagic Release of Labile Iron

“…First, we examined the possibility that GOT1 could be altering phospholipid composition. HIF-2α stabilization has been recently shown to promote a ferroptosis primed cell-state by selectively enriching for polyunsaturated acids in clear-cell carcinomas 38 . This vulnerability was mediated by hypoxia-inducible lipid droplet-associated protein (HILPDA).…”

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

“…This seems plausible since recent studies have elucidated that ROS generated by SOD2 silencing increases HIF1α expression . Just recently, the role of glutathione peroxidase 4 (GPX4), which uses glutathione to selectively detoxify lipid hydroperoxides and acts as a gatekeeper for ferroptosis, an iron‐dependent cell‐death pathway, has been highlighted in clear cell carcinomas, including clear cell RCC . Namely, due to intensified lipid and glycogen synthesis and accumulation, these carcinomas develop intrinsic vulnerability to ferroptosis.…”