The impact of oncogenic RAS on redox balance and implications for cancer development

Abstract

The RAS family of proto-oncogenes comprises HRAS, KRAS, and NRAS, which are among the most mutated genes in human cancers. The RAS family genes encode small GTPases that coordinate key signaling pathways in response to growth factors. Mutations in RAS result in a constitutively active form of the protein that supports cellular transformation and tumorigenesis. The mechanisms of oncogenic RAS-mediated transformation encompass uncontrolled proliferation and inhibition of cell death through overactivation of the RAF-MEK-ERK and the PI3K-AKT pathways, respectively. In addition, the control of redox balance by RAS has also been proposed to play a role in its oncogenic properties. However, the exact role of redox balance in mediating mutant RAS transformation is still under debate. Here, we present, on one hand, the involvement of pro-oxidant components in oncogenic RAS transformation, such as NADPH oxidases and mitochondrial reactive oxygen species, and how these promote transformation. On the other hand, we describe the contribution of antioxidant components to mutant RAS transformation, including Nrf2, glutathione biosynthesis and xCT, as well as the mechanisms by which antioxidant programs drive transformation. Finally, we aim to reconcile the seemingly opposite effects of oncogenic RAS on redox balance and discuss a model for the complementary role of both pro-oxidant and antioxidant pathways in mutant RAS-driven tumor progression.

Fig. 1. Downstream canonical signaling pathways of oncogenic RAS effectors.

RAS signaling is initiated by upstream growth factor receptors and receptors tyrosine kinase (RTK) activation, leading to recruitment of guanine nucleotide exchange factor (GEF) by Src homology 2 domain containing transforming protein (SHC) and growth factor receptor-bound protein 2 (GRB2), which substitutes GDP with GTP to activate RAS. Once in its active state, or in the case of activating mutations, RAS can engage its downstream effectors including but not limited to phosphoinositide 3-kinase (PI3K), rapidly accelerated fibrosarcoma proto-oncogene (RAF), Ral guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C-epsilon (PLCε).

Fig. 2. Signaling pathways and mechanisms driving oncogenic RAS induction of cellular pro-oxidant programs.

Oncogenic RAS drives multiple pro-oxidant programs ranging from activation of subunits of the NADPH oxidase complex (NOX1/4), inactivation of antioxidants such as sestrin 1 (SESN1), or promoting ROS production from the mitochondria or from cyclooxygenase-2 (COX2).

Fig. 3. Signaling pathways and mechanisms driving oncogenic RAS induction of cellular antioxidant programs.

Oncogenic RAS drives multiple antioxidant programs by altering intracellular metabolism, such as by driving GSH and NADPH production via the TCA cycle, by generating NAPDH through an alternative glutamine metabolic pathway mediated by aspartate aminotransferase (GOT1), or potentially by generating NADPH via a fatty acid oxidation pathway mediated by acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3). In addition, oncogenic RAS upregulates several key antioxidant proteins, including the light-chain subunit of the system x_c⁻ transporter (xCT), nuclear factor, erythroid 2-like 2 (NRF2), and gamma-glutamyltransferase 2 (GGT2).

Fig. 4. Proposed model for the role of cellular redox homeostasis in oncogenic RAS-mediated tumor initiation and progression.

Oncogenic RAS activates antioxidant programs at tumor initiation, leading to redox adaptation, proliferation, and transformation, as well as apoptosis resistance. During tumor progression, oncogenic RAS additionally promotes pro-oxidant programs, which drive DNA-damage response activation, de-differentiation, genetic instability, and proliferation.