Bioactive lipids in cancer stem cells

Begicevic, Romana-Rea; Arfuso, Frank; Falasca, Marco

doi:10.4252/wjsc.v11.i9.693

Cited by 29 publications

(19 citation statements)

References 122 publications

(129 reference statements)

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“…Furthermore, many studies have shown that increased lipid synthesis helps to maintain CSCs. It is an important source of metabolic intermediates and energy needed for cell growth and stemness-related pathways 47,[49][50][51][52][53] .…”

Section: Sas Tumour Spheres Demonstrated Enhanced Cisplatin Resistancementioning

confidence: 99%

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin

Leong

et al. 2020

Sci Rep

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Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC). However, the intrinsic or acquired resistance against cisplatin remains a major obstacle to treatment efficacy in OSCC. Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers. However, the role of mtDNA alterations in OSCC has not been comprehensively studied. In this study, we evaluated the correlation between mtDNA alterations (mtDNA content, point mutations, large-scale deletions, and methylation status) and cisplatin sensitivity using two OSCC cell lines, namely SAS and H103, and stem cell-like tumour spheres derived from SAS. By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin. By qPCR analysis, we found that the cells with less mtDNA were less responsive to cisplatin (H103 and the tumour spheres). Based on the findings, we theorised that the metabolic changes in the tumour spheres probably resulted in mtDNA depletion, as the cells suppressed mitochondrial respiration and switched to an alternative mode of energy production, i.e. glycolysis. Then, to ascertain the origin of the variation in mtDNA content, we used MinION, a nanopore sequencer, to sequence the mitochondrial genomes of H103, SAS, and the tumour spheres. We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome. Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response. Cis-diamminedichloroplatinum (II), or cisplatin, is one of the most commonly used chemotherapy agents in the treatment of various solid tumours such as ovarian, colorectal, prostate, lung, and head and neck tumours 1-5. To date, the intrinsic or acquired resistance of cancer cells to cisplatin remains a challenge in the chemotherapy of several cancers including oral squamous cell carcinoma (OSCC) 3,6. OSCC, which affects the epithelial layer of the oral cavity, is a common malignant tumour of the head and neck with low survival rates and high risks of recurrence 7. The well-characterized mode of action of cisplatin is via causing the formation of DNA adducts upon its binding to the nucleophilic N7 sites of purines, which further leads to DNA damage responses and apoptosis 2,6,8. Cisplatin resistance in general involves reduced DNA damage due to an increase in DNA adduct repair, reduced drug uptake, or increased drug inactivation 1,3,4,6. Activation of these mechanisms depends on multiple factors including genetic changes, epigenetic alterations at both molecular and cellular levels, and heterogeneity among cancer cells 4,9,10. The recently proposed cancer stem cells (CSCs) model highlighted tumour heterogeneity as an important basis of treatment resistance and relapse in cancer. According to the model, CSCs comprise a tumourigenic subpopulation where they exhibit stem cell-like features ...

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Section: Sas Tumour Spheres Demonstrated Enhanced Cisplatin Resistancementioning

confidence: 99%

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin

Leong

et al. 2020

Sci Rep

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“…Several lipogenic genes are reprogrammed in CSCs and are critical for CSCs maintenance. Although these mechanisms require further investigation, FAS was found to be involved in CSCs survival in several cancer cell types such as glioma, pancreatic tumors or breast cancer [ 86 ]. Knockdown of ACLY inhibits epithelial–mesenchymal transition, a phenomenon related to cancer stemness [ 87 ].…”

Section: Changes In Lipid Metabolism Contribute To Anticancer Drugmentioning

confidence: 99%

Lipid Metabolism and Resistance to Anticancer Treatment

Germain

Dhayer

Boileau

et al. 2020

Biology

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Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells’ sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.

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“…DGAT2 catalyzes the nal step in synthesis triglyceride, which is a major component of LDs [36], and genetic deletion of DGAT2 was lethal with knockout mice presenting severe and systemic reductions in triglyceride [37]. SCD is a principal enzyme responsible for fatty acid desaturation, which is critical for growth, survival and tumorigenesis [25,38]. ENPP2, also known as Autotaxin (ATX), is always overexpressed in many malignancies [39], including MCL [40].…”

Section: Discussionmentioning

confidence: 99%

Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma

Liu

Zhang

et al. 2021

Preprint

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Background: The more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown.Methods: AlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis.Results: Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. Conclusion: BTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

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Bioactive lipids in cancer stem cells

Cited by 29 publications

References 122 publications

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Lipid Metabolism and Resistance to Anticancer Treatment

Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma

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