Targeting Cancer Stem Cell Redox Metabolism to Enhance Therapy Responses

Abstract

Cancer has long been viewed as a disease of altered metabolism. Although it has long been recognized that the majority of cancer cells display increased dependence on glycolysis, the metabolism of "cancer stem-like cells" (CSCs) that drive tumor growth and metastasis is less well characterized. In this chapter, we review the current state of knowledge of CSC metabolism with an emphasis on the development of therapeutic strategies to exploit the metabolic vulnerabilities of these cells. We outline emerging evidence indicating distinct metabolic pathways active in the proliferative, epithelial- (E) and quiescent, mesenchymal-like (M) CSC states in triple negative breast cancer. These CSC states are characterized by their different redox potentials and divergent sensitivities to inhibitors of glycolysis and redox metabolism. We highlight the roles of two redox-regulated signaling pathways, hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2, in regulating CSC epithelial-mesenchymal plasticity during metabolic and/or oxidative stress, and discuss clinical strategies using combinations of pro-oxidant-based therapeutics simultaneously targeting E- and M-like CSCs. By specifically targeting CSCs of both states, these strategies have the potential to increase the therapeutic efficacy of traditional chemotherapy and radiation therapy.

Figure 1.. Metabolic differences of E- and M-BCSCs versus the bulk tumor cells.

The CD24⁻CD44⁺ M-BCSCs and ALDH⁺E-BCSCs significant differ in many aspects of cellular metabolism as compared to the bulk tumor cells identified as ALDH⁻CD24⁺CD44⁻.

Figure 2.. A pro-oxidant based therapeutic approach with potential to increase treatment responses for traditional cancer therapies.

Combination strategies utilizing traditional cancer therapies (i.e., standard radio-chemotherapies or anti-angiogenic therapies) in combination with inhibitors of NRF2-mediated antioxidant responses (i.e., NRF2 inhibitor Trig or inhibitors of TXN/GSH antioxidant pathways including AUR/BSO) enhance treatment responses by simultaneously targeting CSCs of distinct states.

Figure 3.. NRF2 acts as a central hub to facilitate the transition of BCSCs from the M to E state as well as the maintenance/proliferation of E-BCSCs under metabolic/oxidant stress.

The activation of NRF2 during metabolic/oxidant stress promotes CSC plasticity by mediating AMPK-dependent HIF1α stabilization, which is required for the conversion of M- to E-BCSCs. NRF2 activation also mediates the activation of HIF1α-NOTCH self-renewal pathway and the expression of NRF2 target genes ALDH1A1/3 to facilitate the propagation of E-BCSCs.