Under metabolic stress, the redox balance is damaged. Limited glucose sources impair glycolysis, and glycolysis-based NADPH production is depleted by reduced utilization of the PPP [
34]. Additionally, glucose limitation leads to overburdening of mitochondria energy production. As a result, the metabolism rewires from glycolysis to OXPHOS and subsequent pro-oxidant production, primarily superoxide and hydrogen peroxide, leads to ROS overload [
35,
36]. The disequilibrium of ROS production over ROS scavenging leads to ROS stress (Fig.
1b), which further activates apoptotic pathways. A study by NA Graham et al. based on phospho-tyrosine proteomics showed that metabolic stress provoked a supra-physiological level of TKR signaling, causing a positive feedback loop between ROS, PTPs and TKR signaling, and ultimately leading to cell death [
37]. Meanwhile, by using ROS scavenger N-acetylcysteine (NAC), the kinase activation could be reversed under glucose deprivation [
38,
39]. In addition, it is reported in M Gao’s study that Reverse Phase Protein Arrays (RPPA) analysis detected the signal change after glucose deprivation. A variety of kinases were activated, which was consistent with NA Graham’s study [
37]. Interestingly, though the study of M Gao exhibited a dramatic difference in the spectrum of activated kinases between transient and prolonged glucose deprivation [
40]. It was hypothesized that the kinase activation after glucose deprivation and its role in cell survival might be time-dependent and specific to cell lines. These studies underline the importance of the kinase activation loop in mediating ROS-induced cell death.
Although Otto Warburg, who proposed the theory of the Warburg effect, declares mitochondrial dysfunction leads to prevalent use of glycolysis in cancer cells, there are studies suggesting that many cancer cells prioritize OXPHOS to generate ATP [
41]. It is generally agreed that enhanced glycolysis in cancer cells does not necessarily correspond to impaired OXPHOS [
32]; particularly under metabolic stress, mitochondrial-based energy production is essential for viability. Under metabolic stress, other intermediates like glutamine [
42,
43], lactate [
44,
45], fatty acids and others [
7,
46] are alternatively consumed to produce ATP. J Yun et al. reported that colorectal cancer cells demonstrated higher expression of KRAS and GLUT1 under glucose deprivation [
47]. Additionally, glucose deprivation stimulated the tricarboxylic acid (TCA) cycle through mitochondrial glutamine metabolism, which was a source of ATP and generated a-ketoglutarate (α-KG) for biosynthesis [
43,
48]. However, enhanced mitochondrial burden under metabolic stress increases the ROS production. The conflicts of producing energy versus maintaining ROS homeostasis dramatically impacts the fate of cancer cells.