Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells

Naik, Prajna Paramita; Panigrahi, Swagatika; Parida, Ratnakar; Praharaj, Prakash Priyadarshi; Bhol, Chandra Sekhar; Patil, Shankargouda; Manjunath, N; Ghosh, Dipanjan; Patra, Samir Kumar; Bhutia, Sujit K.

doi:10.1007/s12015-021-10216-9

Cited by 8 publications

(10 citation statements)

References 171 publications

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“…In iPSCs, the role of mitophagy has been associated with cell fate conversion, which involves a significant reduction in mitochondrial mass and numbers compared with parental somatic cells [ 112 , 113 ]. The crucial role of PINK1-dependent mitophagy has been identified in the reprograming of iPSCs and maintenance of pluripotency, indicating that mitophagy is directly responsible for determining the fate of SCs [ 114 ].…”

Section: Mitochondrial Autophagy: Mitophagy In Cscsmentioning

confidence: 99%

Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells

Tiwari,

Srivastava,

Abbas

et al. 2024

Cells

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Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence.

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Section: Mitochondrial Autophagy: Mitophagy In Cscsmentioning

confidence: 99%

Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells

Tiwari,

Srivastava,

Abbas

et al. 2024

Cells

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“…The glutamine uptake in CSCs has also been associated with upregulation of alanine, serine, cysteine-referring transporter 2 (ASCT2). Glutamate oxaloacetate transaminases (GOT1 and GOT2), enzymes that are responsible for converting glutamate-derived aspartate to oxaloacetate, also show an elevated expression in CSCs ( 54 ).…”

Section: Metabolic Profile Of Cscsmentioning

confidence: 99%

“…Reprogramming of metabolic cofactors also possesses significant alterations in chromatin remodeling from the aspect of CSCs. Metabolic cofactors like NAD, FAD, PARP, SAM, LSD1, Coenzyme A have shown transformational changes in chromatin structure ( 54 , 165 ). PGC-1α has been known to be associated with SIRT1 and AMPK to perturb the metabolic stature of cells.…”

Section: Epigenetic Regulations Of Stemness Of Cscs In Few Cancersmentioning

confidence: 99%

“…In addition, this SIRT1 has been seen to facilitate NAD+ dependent deacetylation of target molecules and orchestrate metabolic agitations by stimulating transcriptional factors like PPARs, p53, FOXO etc. NAD+/NADH ratio also helps in maintaining stemness features, mitochondrial quality, and active aerobic glycolysis, thus highlighting the significance of SIRT1 as a metabolic game-changer ( 54 ). Other factors like BAF/PBAF also regulate the energy metabolism pathways in cancer, thereby being a critical regulator of metabolic homeostasis ( 166 ).…”

Section: Epigenetic Regulations Of Stemness Of Cscs In Few Cancersmentioning

confidence: 99%

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The metabolic addiction of cancer stem cells

et al. 2022

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Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg’s aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate “onco-metabolites” that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.

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“…It is well documented that CSCs are highly resistant to conventional chemotherapies [ 11 , 26 - 32 ] and target specific anticancer agents. Figure 3 shows that various drug resistance mechanisms have been reported in CSCs including increased anti-apoptotic proteins such as Bcl-2 Bcl-X, and c-FLIP [ 11 , 26 ] , high expression of ATP-binding cassette (ABC) transporter proteins and detoxifying enzymes [ 26 - 28 ] , cell cycle quiescence [ 29 , 30 ] , increased DNA repair ability [ 26 , 27 ] , elevated aldehyde dehydrogenase (ALDH) activity [ 31 ] , activation of key prosurvival signaling molecules such as Notch, Wnt/β-catenin, and NF-κB [ 32 - 34 ] , increased activities of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and maternal embryonic leucine zipper kinase (MELK), aberrant stemness signaling pathways, increased quiescence, and increased autophagy [ 11 , 35 ] .…”

Section: Introductionmentioning

confidence: 99%

Drug and apoptosis resistance in cancer stem cells (CSCs): A puzzle with many pieces

Safa¹

2022

Cancer Drug Resist

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Resistance to anti-cancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anti-cancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal (EMT) progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment (TME) creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), Bcl-2 family members, inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

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Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells

Cited by 8 publications

References 171 publications

Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells

Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells

The metabolic addiction of cancer stem cells

Drug and apoptosis resistance in cancer stem cells (CSCs): A puzzle with many pieces

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