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

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Hypoxia is a hallmark of solid tumors which promotes tumor cell growth, survival, metastasis and confers resistance to chemo and radiotherapies. Targeting hypoxic cells has been difficult. Moreover, inhibitors for the major transcription factors, hypoxia inducible factor (HIF)-1 and HIF-2 have not shown long-term efficacy in most cancers. We have previously shown that HIF-2 is essential for colon tumorigenesis.Using an unbiased screen, we show a significant increase in synthetic lethality of HIF-2 overexpressing tumor enteroids to oxidative cell death activators. The treatment with hypoxia mimetic FG4592 (Roxadustat), led to a robust increase in erastin-, RSL3-, and dimethyl fumarate-induced cell death in a dose-and time-dependent manner. Further, our in-vitro data shows that HIF-2 knock-down cells are completely resistant to these drugs. HIF activation promotes upregulation of lipid synthesis genes in vitro and in vivo leading to oxidative stress. Taken together, our results suggest that this intrinsic sensitivity towards oxidative stress associated with hypoxia could be utilized as a persistent and dynamic form of cell death for colon cancer treatment.

Ferroptosis, radiotherapy, and combination therapeutic strategies

“…5A). Mechanistically, HIF-2ɑ activates hypoxia-induced, lipid droplet-associated protein (HILPDA) to promote the formation of PUFA-PLs and thereby increase the susceptibility of cancer cells to ferroptosis (Singhal et al, 2019;Zou et al, 2019). HIF-1ɑ activation also sensitizes renal cancer cells to ferroptosis (Zou et al, 2019).…”

Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit

“…Cancer cell lines from several lineages exhibit intrinsic sensitivity to ferroptosis, including clear-cell renal cell and ovarian carcinoma (Miess et al, 2018;Zou et al, 2019a), triple-negative breast cancer (Doll et al, 2017), adrenocortical carcinomas (Belavgeni et al, 2019), diffuse large B cell lymphoma (Yang et al, 2014), and cancer cells from the liver (Louandre et al, 2013;Sun et al, 2016), pancreas (Badgley et al, 2020), and colorectum (Singhal et al, 2019). Moreover, susceptibility to ferroptosis can be acquired during cell-state transitions in cancer, such as the development of therapy resistance (Hangauer et al, 2017;Viswanathan et al, 2017;Tsoi et al, 2018).…”

“…In renal cell carcinoma cells, hypoxia-inducible factor 2ɑ (HIF-2ɑ) positively and selectively regulates PUFA lipids by activating hypoxia-induced, lipid droplet-associated protein (HILPDA) (Zou et al, 2019a) (Figure 2), although the biochemical basis for HILPDA's PUFA selectivity remains unclear. The proferroptosis role of HIF-2ɑ is recapitulated in colorectal cancers (Singhal et al, 2019). Considering the complex physiological roles of polyunsaturated lipids, cells likely shape their PUFA lipidome by their intrinsic cell states and by responding to environmental stimuli.…”