Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy

Abstract

HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.

RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study

“…While Epistolio et al suggest that inflammation and neo-angiogenesis can be taken in consideration as speculative selective pressure mechanisms, we hypothesize that it might depend on the ability of bevacizumab to maximally increase oxidative stress. In fact, although RAS-driven tumors strongly rely on increased reactive oxygen species (ROS) production to maintain their transformed state, a massive intracellular ROS increase is inefficiently scavenged in RAS mutant cells, leading to their selective ferroptosis, a kind of oxidative death [26,27]. Thus, being RAS-driven cancers particularly committed to keeping ROS levels within certain limits to be never exceeded, a viable strategy to target RAS mutant cancers is to sensitize cells to exogenous ROS inducers, shifting the redox state so that cells can no longer appropriately respond to further oxidative stress.…”

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

“…Cancer cells have an abnormal ROS homeostasis ( 47 ); if on one hand ROS promote tumorigenesis, on the other, exceeding ROS “threshold” is toxic and might trigger several cell death mechanisms including apoptosis, senescence and ferroptosis ( 48 , 49 ). By interacting with lipids, ROS induce the peroxidation of fatty acids both in an enzymatic and non-enzymatic way, altering membrane permeability and promoting the formation of lipid hydroxides and other high reactive aldehydes such as 4-hydroxy-2-non-enal (4-HNE), acetaldehyde, malondialdehyde (MDA) and 4-hydroxy-2-hexenal (4-HHE) ( 50 ). The resulting macromolecular damage promotes the activation of a wide range of DNA damage repair pathways, including nucleotide excision repair (NER), base excision repair (BER), homologous recombination (HR), and ATR/ATM cell cycle checkpoints ( 51 ).…”

Establishment and Validation of a Ferroptosis-Related Long Non-Coding RNA Signature for Predicting the Prognosis of Stomach Adenocarcinoma

“…CAV1 can promote cancer progression via inhibiting ferroptosis in head and neck squamous cell carcinoma ( Lu et al, 2022 ) and drives the execution of acute immune-mediated hepatic damage ( Deng et al, 2020 ). KRAS can promote the generation of ROS, thereby promoting the accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis ( Bartolacci et al, 2021 ). GPX4 can reduce phospholipid hydroperoxide to hydroxy phospholipid, thus inhibiting ferroptosis in cancer cells ( Yang et al, 2014 ).…”