Role of Mitochondria in Cancer Stem Cell Resistance

Abstract

Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the ability of this organelle to modify cell metabolism, allowing survival and avoiding apoptosis clearance of cancer cells. Thus, the whole mitochondrial cycle, from its biogenesis to its death, either by mitophagy or by apoptosis, can be targeted by different drugs to reduce mitochondrial fitness, allowing for a restored or increased sensitivity to chemotherapeutic drugs. Once mitochondrial misbalance is induced by a specific drug in any of the processes of mitochondrial metabolism, two elements are commonly boosted: an increment in reactive nitrogen/oxygen species and, subsequently, activation of the intrinsic apoptotic pathway.

Keywords: cancer stem cells; drug resistance; metabolic plasticity; mitochondria.

Figure 1

Mitochondrial biogenesis misbalance in cancer stem cells (CSCs). In normal cells, mitochondrial mass is usually maintained. However, both increased mitochondrial biogenesis, on the one hand, and alterations on mtDNA, on the other hand, are connected with an increased resistance in CSCs. Black arrows refer to increased chemoresistance, from a normal situation where mitochondrial biogenesis allows the maintenance of mitochondrial population. Treatment with antibiotics of CSCs with high mitochondrial biogenesis can overcome chemoresistance (red arrow), but prolonged treatments can force the appearance of a CSC population with reduced mtDNA (dotted red arrow).

Figure 2

Mitochondrial metabolism targeting can overcome CSC resistance. (A) Mitochondrial eltron transport chain (ETC), core of oxidative metabolism, showing some of the described inhibitors for each complex (blue lines) used for CSC treatment. CI: complex I; CII: complex II; CIII: Complex III, CIV: Complex IV; CV: Complex V; Q: ubiquinone; Cc: cytochrome c. Outer mitochondrial membrane appears in red, while inner mitochondrial membrane is colored in grey. Salinomycin causes mitochondrial membrane potential (ΔΨm) disruption. (B) Reactive oxygen species produced as a consequence of ETC. Inhibitors of mitochondrial detoxifying enzymes are labelled with a blue line. Red arrow indicates a RNOS enhancer. ATO: Arsenic trioxide; GSH: glutathione; GSSG: glutathione disulfide; GR: glutathione reductase; GPX: gluthathione peroxidase. (C) Glycolytic metabolism, showing inhibitors of GLUT1 and hexokinase, blocking glycolysis at its beginning, and dichloroacetate (DCA), that inhibits pyruvate dehydrogenase kinase (PDK) and allow the incorporation of pyruvate into the tricarboxylic acid (TCA) cycle. Blue lines correspond to glycolytic inhibitors, while red arrows belong to HIF-1α, a glycolytic enhancer. 2-DG: 2-deoxyglucose; GPI: glucose-6-phosphate isomerase; G3PDH: glyceraldehyde-3-phosphate dehydrogenase; PGK1: phosphoglycerate kinase; PGM: phosphoglycerate mutase. (D) Summary of fatty acid oxidation (FAO) metabolism. Etomoxir and perhexiline, inhibitors of CPT1 (blue line) diminished CSC population, by reducing mitochondrial incorporation of fatty acids. (E) Pathways related to the TCA cycle frequently modified in CSCs. Blue arrows correspond to aconitase (ACO) knockdown. SDH: succinate dehydrogenase; FH: fumarate hydratase; IDH: isocitrate dehydrogenase; mIDH: mutated IDH. GLS: glutaminase; GDH: glutamate dehydrogenase; IDH: isocitrate dehydrogenase; ACLY: ATP citrate lyase.

Figure 3

Mechanism of mitophagy. Mitochondrial fission is induced after DRP1 recruitment in mitochondria, a process that can be inhibited by targeting DRP1. Mitochondrial engulfment to form the mitophagolysosome can be inhibited in different steps. Thus, double membrane formation can be inhibited by drugs such as 3-methyladenine or LY294002, while it is enhanced by doxorubicin. Once the mitophagosome is formed, its fusion with lysosome can be inhibited by drugs like bafilomycin A, leupeptin or liensinine, or inhibiting lysosome formation by drugs like mefloquine or chloroquine. Blue lines correspond to autophagy/mitophagy inhibitors, red arrows refer to mitophagy activators.

Figure 4

Summary of intrinsic apoptotic pathway. BCL-2, as antiapoptotic protein, inhibits the formation of pores by BAX/BAK that allow cytochrome c release to the cytoplasm, where it interacts with Apaf-1 to constitute apoptosome, allowing caspase cascade. Drugs targeting apoptosis comprise dissipaters of mitochondrial membrane potential (ΔΨm) or BCL-2 inhibitors (blue lines) or molecules enhancing formation of BAX/BAK pores (red arrow).