The double-edged roles of ROS in cancer prevention and therapy

Abstract

Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.

Figure 1

The primary generation and elimination mechanisms of intracellular ROS. (Ⅰ) The two major sources of endogenous ROS are mitochondrial ETC and NOXs: oxygen gains electrons leaked from complex Ⅰ, Ⅱ and Ⅲ of ETC to generate superoxide; NOXs transfer electrons from NADPH in the cytosol to oxygen at extracellular to produce superoxide; superoxide is dismutated to H₂O₂ by SOD for subsequent transmembrane transportation. (Ⅱ) Intracellular ROS are scavenged by three enzymatic antioxidants: PRXs, GPXs and CAT. PRXs and GPXs use NADPH as reducing equivalent; CAT use non-NADPH hydrogen donors. (Ⅲ) NADPH is synthesized in cytoplasm and mitochondria: cytosolic NADPH is primarily generated from PPP pathway; in mitochondria, GLUD generate NADPH by converting glutamate to α-KG; IDHs and MEs are contributed to NADPH pools both in the cytosol and mitochondrial by respectively catalyzing the oxidative decarboxylation of isocitrate to α-KG and malate to pyruvate; one-carbon metabolism contributes to NADPH production both in cytosol and in mitochondria.

Figure 2

The carcinogenic effects of ROS. (Ⅰ) ROS drive proliferation by activating of PI3K/AKT/mTOR and MAPK mitogenic signaling cascades: the devitalized oxidation of PTEN and PTP1B impair their inhibition on PI3K and cause the hyper-activation of AKT and mTOR; ROS accumulation can respectively activate ASK1, PKG and JNK to further stimulate the downstream MAPKK and MAPK mitosis cascades. (Ⅱ) ROS participate in cancer cell EMT: RAC1 not only directly affects cytoskeleton rearrangement but also up-regulates FAK or inhibits RhoA expression through ROS generation to promote cytoskeleton rearrangement; ROS pile up increases MMP expression by activating NF-κB phosphorylation to enhance ECM degradation; ROS suppress HIF ubiquitin degradation and promote its interaction with p300 to induce angiogenesis.

Figure 3

ROS induce cell death, mainly including apoptosis, necroptosis and ferroptosis. (Ⅰ) Exceeding ROS promote both the extrinsic and intrinsic apoptosis pathway: ROS activate extrinsic apoptosis pathway by accelerating the ubiquitin degradation of c-FLIP, then enhancing the binding between the adaptor protein and pro-caspase-8; ROS induce intrinsic apoptosis by facilitating the release of Cyt-c from mitochondria to cytoplasm to form apoptosome with casp-9 and APAF-1. (Ⅱ) ROS and necroptosis form a positive feedback loop: ROS stabilize RIP3 protein to lead to the formation of DISC Ⅱb (necrosome); in turn, RIP3 can facilitate the TCA cycle and aerobic respiration in mitochondria to induce ROS generation. (Ⅲ) Ferroptosis is a ROS-dependent form of RCD: the basic of ferroptosis is GSH anabolism disorder leads to the lethal accumulation of PUFAs peroxidation; p53 plays opposite roles on ROS and ferroptosis by inhibiting SLC7A11 expression or increasing NADPH production.