Mitochondria in Cancer Stem Cells: From an Innocent Bystander to a Central Player in Therapy Resistance

Figures & data

Table 1 Cancer Stem Cell Associated Markers Reported in Different Cancers

Cancer Type	Markers of CSCs
Breast	CD44, CD24, ALDH1A1, ESA, CD61, CD90, CD49f, CD29, LGR5, CD13, NANOG, KLF4, SOX2, BMI1, CXCR4, OCT4, SALL4, CD29, CD133
Cervical	CD44, CD29, CD13, CD105, ABCG2, CD133, CD49f, ALDH
Prostate	CD44, ALDH1A1, CD133, α2β1, CD49f, CD166, NANOG, KLF4, SOX2, BMI1, OCT4, SALL4, CD151, EpCAM, CD117, α2β1, EZH2, CXCR4, E-cadherin
Colorectal	CD44, CD24, ALDH1A1, CD133, ESA, CD166, CD29, CD26, LGR5, NANOG, KLF4, SOX2, Musashi-1, BMI1, SALL4, LETM1, CD200, EpCAM, CD206, CD49f
Ovarian	CD44, CD24, ALDH1A1, CD133, ESA, CD117, NANOG, SOX2, OCT4, SALL4, CD105, EpCAM
Lung	CD133, ALDH1, CD44, CD24, ALDH1A1, ESA, CD34, CD90, CD117, CD166, NANOG, SOX2, BMI1, OCT4, CD87, CD133
Liver	CD44, CD24, ALDH1A1, CD133, ESA, CD90, CD117, CD49f, CD13, OCT4, AFP, CD206, OV-6, EpCAM
Head/Neck	CD44, CD24, ALDH1A1, CD133, CD90, LGR5, BMI1, CD271, CD166
Pancreatic	CD1333, CXCR4, SSEA-1, CD44, CD24, CD133, ESA, Nestin, SOX2, BMI1, CXCR4, OCT4, ALDH, ABCG2
Leukemia	ALDH1A1, NANOG, KLF4, SOX2, BMI1, OCT4, CD47
Gastric	CD44, HER2, APC, p53, KRAS, PTEN, LGR5, CCKBR, RHOA, CDH-1, SMAD5, ATP4B, PGA3, CD24, ALDH1A1, CD133, ESA, CD90, NANOG, SOX2, CXCR4, CD15, LINGO2, LETM1, MSI2, CD54, CD49f, CD71, EpCAM
Bladder	CD44, OCT4, CD47, CD66c, CD44v6, ALDH
Brain	CD44, CD133, ESA, SSEA-1, CD90, CD49f, NANOG, KLF4, Nestin, SOX2, Musashi-1, BMI1, CXCR4, CD15, CD36, EGFR, A2B5, L1CAM
Melanoma	CD133, CD166, Nestin, SOX2, OCT4, CD20, ABCB5, CD271, ALDH
Renal	CD133, ALDH, CXCR4, CD44, CD105
Gall bladder	CD44/CD133
Oral	CD44^+/CD24^−, ITGA7
Esophageal	ITGA7, CD44, ALDH, CD133, CD90
Nasopharyngeal	CD44, CD133, ALDH, CD24
Laryngeal	ALDH, CD44, CD133
Multiple myeloma	CD19, CD27
Blood	CD34, CD38, CD123, CD90, CD117, CD26, CD20, TIM3, SALL4, CD19

Figure 1 Mitochondrial Dysfunction and Cancer Stem Cells (CSCs). (a) Schematic of mitochondrial biogenesis and its regulation by transcription factors (PGC1, NRF, TFAM, PPAR, and ERR). Additionally, depicted are AMPK, oncogenic KRAS, and c-MYC-dependent mechanisms that lead to increase in biogenesis and energy production. This results in elevated oxidative phosphorylation (OXPHOS) and high ATP levels in CSCs. (b) Representation of mitochondrial metabolic dependency in CSCs. Cellular energy is derived through OXPHOS, fatty acid oxidation (FAO), and the TCA cycle within the mitochondria. CSCs exhibit increased oxidative phosphorylation for enhanced ATP production and elevated fatty acid oxidation through activation of oncogenic pathways. Deregulated TCA cycle enzymes in CSCs produce oncometabolites contributing to cancer progression. (c) Representation of altered mitochondrial dynamics in CSCs, where the balance between mitochondrial fission and fusion is disrupted. Upregulation of mitochondrial fission proteins (Drp1) and their regulators (Fis1, MID49, MID51, MFF) and downregulation of mitochondrial fusion proteins (Mfn1, Mfn2, OPA1) leads to impaired mitochondrial dynamics. (d) Increased activity of Ca²⁺-dependent kinases (PKC, CaN, CAMKIV, JNK, MAPK) due to altered membrane potential in CSCs is shown. Also indicated are the kinases and nuclear transcription factors involved in retrograde signaling. (e) Schematic representation of mitophagy in CSCs. Elevated cytoplasmic PINK1 phosphorylates Parkin and ubiquitinated-OMM proteins. Phosphorylated Parkin is transported into the mitochondria where it ubiquitinates itself and other mitochondrial substrates. These ubiquitin (Ub)-marked mitochondria are degraded by autophagosomes. (f) Mitochondria-mediated apoptosis in CSCs. Cells with damaged DNA activate caspase-8 mediated cell death. In CSCs, activation of caspase-8 is inhibited by high levels of c-FLIP; levels of pro-apoptotic proteins (Bax, Bak) are decreased while levels of anti-apoptotic proteins (Bcl-xL) are increased leading to cell survival and no apoptosis.

Table 2 Drug Category and Mode of Acquired Resistance in Cancer Stem Cells in Different Cancers

Drug	Cancer Type	Impact of the Molecule Involved	Mode of Action	Ref.
Metformin	Pancreatic	Reduced MYC and increased PGC-1α levels	Lowers ROS levels	[190]
Paclitaxel	Triple Negative Breast Cancer	Increased expression of Myc	Increased mtOXPHOS and ROS levels	[191]
Sorafenib	Hepatocellular	Increased NANOG	Increased FAO	[192]
Gefinitib	Non Small Cell Lung Cancer	Increased expression of HIF-1	Increased IGF1 expression	[193]
Gefinitib	Non Small Cell Lung Cancer	Loss of PTEN	Akt activation; increased TSPYL5 expression	[194]
Temozolomide	Glioma	Loss of PTEN	Promotes SP phenotype	[195]
Paclitaxel & gemcitabine	Triple Negative Breast Cancer	Increased expression of HIF	Increased IL-6 and IL-8 signaling; Increased MDR expression	[196]
Doxorubicin	Breast	Overexpression of Bcl-2	Upregulation of IL-6/STAT3 pathway	[124]

Sancho P, Burgos-Ramos E, Tavera A, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 2015;22:590–605. PMID: 26365176. doi:10.1016/j.cmet.2015.08.015

 PubMed Web of Science ®Google Scholar

Lee K-M, Giltnane JM, Balko JM, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633–647.e7. PMID: 28978427. doi:10.1016/j.cmet.2017.09.009

 PubMed Web of Science ®Google Scholar

Chen C-L, Uthaya Kumar DB, Punj V, et al. NANOG metabolically reprograms tumor-initiating stem-like cells through tumorigenic changes in oxidative phosphorylation and fatty acid metabolism. Cell Metab. 2016;23:206–219. PMID: 26724859. doi:10.1016/j.cmet.2015.12.004

 PubMed Web of Science ®Google Scholar

Murakami A, Takahashi F, Nurwidya F, et al. Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. PLoS One. 2014;9:e86459. PMID: 24489728. doi:10.1371/journal.pone.0086459

 PubMed Web of Science ®Google Scholar

Kim I-G, Lee J-H, Kim S-Y, Heo C-K, Kim R-K, Cho E-W. Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop. Commun Biol. 2021;4:778. PMID: 34163000. doi:10.1038/s42003-021-02303-x

 PubMed Web of Science ®Google Scholar

Bleau A-M, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell. 2009;4:226–235. PMID: 19265662. doi:10.1016/j.stem.2009.01.007

 PubMed Web of Science ®Google Scholar

Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci U S A. 2014;111:E5429–5438. PMID: 25453096. doi:10.1073/pnas.1421438111

 PubMed Web of Science ®Google Scholar

Hu Y, Yagüe E, Zhao J, et al. Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer. Cancer Lett. 2018;423:47–59. PMID: 29496539. doi:10.1016/j.canlet.2018.02.036

 PubMed Web of Science ®Google Scholar