Lovastatin Inhibits Cancer Stem Cells and Sensitizes to Chemo- and Photodynamic Therapy in Nasopharyngeal Carcinoma

Peng, Yunsong; He, Guangchun; Tang, Dehua; Li, Xiong; Wen, Yu; Miao, Xiangshui; Hong, Zhangyong; Yao, Hui; Chen, Chao; Yan, Shichao; Lu, Lu; Yang, Yingke; Li, Qinglong; Deng, Xiyun

doi:10.7150/jca.19100

Cited by 34 publications

(24 citation statements)

References 39 publications

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“…20 In fact, drug-resistant cell populations have more CSCs, 21,22 which are more resistant to conventional cancer therapies than the non-CSC subpopulation. 23 CSCs mediate patients' drug resistance through several different mechanisms. Studies of pancreatic cancer have revealed that there is a definite correlation between EMT-activated CSCs and tumor drug resistance.…”

Section: Discussionmentioning

confidence: 99%

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Liu¹,

Chen²,

Han³

et al. 2020

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Background: Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive. Methods: In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, β-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC. Results: The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial-mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib. Conclusion: LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.

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Section: Discussionmentioning

confidence: 99%

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Liu¹,

Chen²,

Han³

et al. 2020

OTT

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“…Cholesterol synthesis through the mevalonate pathway can be inhibited by statins, for which the molecular target is the enzyme 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-COAR). In fact, treatment with different statins decreased self-renewal and CSCs content in breast (Ginestier et al, 2012) and nasopharyngeal (Peng et al, 2017) carcinomas. Interestingly, similar effects were detected in CD133 + brain TICs (Wang et al, 2017a) where overexpression of mevalonate pathway genes was controlled by MYC, highlighting the variety of metabolic pathways controlled by the oncogene.…”

Section: Therapeutic Targeting Of Cscs Metabolismmentioning

confidence: 99%

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

et al. 2019

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Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.

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“…The second group of lipid-lowering drugs, which have been proved to have anticancer properties are statins (i.e. Lovastatin) (Peng et al, 2017). The mechanism statins action involves the disruption of cholesterol biosynthesis, decrease of cell proliferation and survival (Martirosyan et al, 2010).…”

Section: Lipid Membranes As a Therapeutic Targetmentioning

confidence: 99%

Lipid composition of the cancer cell membrane

Szlasa

Zendran

Zalesińska

et al. 2020

J Bioenerg Biomembr

264

191

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Cancer cell possesses numerous adaptations to resist the immune system response and chemotherapy. One of the most significant properties of the neoplastic cells is the altered lipid metabolism, and consequently, the abnormal cell membrane composition. Like in the case of phosphatidylcholine, these changes result in the modulation of certain enzymes and accumulation of energetic material, which could be used for a higher proliferation rate. The changes are so prominent, that some lipids, such as phosphatidylserines, could even be considered as the cancer biomarkers. Additionally, some changes of biophysical properties of cell membranes lead to the higher resistance to chemotherapy, and finally to the disturbances in signalling pathways. Namely, the increased levels of certain lipids, like for instance phosphatidylserine, lead to the attenuation of the immune system response. Also, changes in lipid saturation prevent the cells from demanding conditions of the microenvironment. Particularly interesting is the significance of cell membrane cholesterol content in the modulation of metastasis. This review paper discusses the roles of each lipid type in cancer physiology. The review combined theoretical data with clinical studies to show novel therapeutic options concerning the modulation of cell membranes in oncology.

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Lovastatin Inhibits Cancer Stem Cells and Sensitizes to Chemo- and Photodynamic Therapy in Nasopharyngeal Carcinoma

Cited by 34 publications

References 39 publications

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

Lipid composition of the cancer cell membrane

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