Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Ishikawa, T.; Hosaka, Yoshinao Z.; Beckwitt, Colin H.; Wells, Alan; Oltvai, Zoltán N.; Warita, Katsuhiko

doi:10.18632/oncotarget.25448

Cited by 22 publications

(17 citation statements)

References 53 publications

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“…Upregulation of genes involved in cholesterol biosynthesis and HMGCR as a mechanism of cells’ resistance was confirmed and extended also by another study. It was shown 58 that the downregulation of HMGCR expression by siRNA in epithelial and mixed epithelial-mesenchymal cells improved cells’ sensitivity to atorvastatin’s growth inhibitory effect. That effect is mainly associated with blockade of isoprenoid synthesis.…”

Section: Statins and Mechanisms Of Resistancementioning

confidence: 99%

Attempts to use statins in cancer therapy: An update

2020

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Although it could be speculated that almost everything has been said concerning the use of statins in cancer therapy, statins as anticancer drugs have both committed supporters and opponents, for whom the dispute about the legitimacy of statin use in cancer treatment seems never to be clearly resolved; every year more than 300 reports which deepen the knowledge about statins and their influence on cancer cells are published. In this mini-review, we focus on the latest (since 2015) outcomes of cohort studies and meta-analyses indicating statin effectiveness in cancer treatment. We discuss attempts to improve the bioavailability of statins using nanocarriers and review the effectiveness of statins in combined therapies. We also summarise the latest results regarding the development of mechanisms of resistance to statins by cancer cells and, on the other hand, give a few examples where statins could potentially be used to overcome resistance to commonly used chemotherapeutics. Finally, special attention is paid to new reports on the effect of statins on epithelial–mesenchymal transition.

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Section: Statins and Mechanisms Of Resistancementioning

confidence: 99%

Attempts to use statins in cancer therapy: An update

2020

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“…Sánchez et al [47] highlighted the antiproliferative effect of HMGCR inhibitors atorvastatin, fluvastatin and simvastatin on MCF-7 breast cancer cells; This effect was associated with a decrease in DNA synthesis and cell cycle arrest in the G1 and G2/M phases. A recent study of Ishikawa et al [48] has shown that HMGCR inhibitor statin inhibits the proliferation and migration of cancer cells, as well as the formation of metastases. The effect of 4-cholesten-3-one on HMGCR expression was examined in MCF-7 and MDA-MB-231 cells and a decrease in mRNA expression was observed, suggesting that cholesterol synthesis was downregulated in our cell models treated with 4-cholesten-3-one.…”

Section: Discussionmentioning

confidence: 99%

4-cholesten-3-one decreases breast cancer cell viability and alters membrane raft-localized EGFR expression by reducing lipogenesis and enhancing LXR-dependent cholesterol transporters

et al. 2019

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Background The alteration of lipid metabolism in cancer cells is recognized as one of the most important metabolic hallmarks of cancer. Membrane rafts defined as plasma membrane microdomains enriched in cholesterol and sphingolipids serve as platforms for signaling regulation in cancer. The main purpose of this study was to evaluate the effect of the cholesterol metabolite, 4-cholesten-3-one, on lipid metabolism and membrane raft integrity in two breast cancer cell lines, MCF-7 and MDA-MB-231. Its ability to reduce cell viability and migration has also been investigated. Methods RT-qPCR was performed to evaluate the expression of enzymes involved in lipogenesis and cholesterol synthesis, and ABCG1 and ABCA1 transporters involved in cholesterol efflux. Its effect on cell viability and migration was studied using the MTT assay, the wound healing assay and the Transwell migration assay, respectively. The effect of 4-cholesten-3-one on membrane rafts integrity was investigated by studying the protein expression of flotillin-2, a membrane raft marker, and raft-enriched EGFR by western blot. Results Interestingly, we found that 4-cholesten-3-one treatment decreased mRNA expression of different enzymes including ACC1, FASN, SCD1 and HMGCR. We further demonstrated that 4-cholesten-3-one increased the expression of ABCG1 and ABCA1. We also found that 4-cholesten-3-one decreased the viability of MCF-7 and MDA-MB-231 cells. This effect was neutralized after treatment with LXR inverse agonist or after LXRβ knockdown by siRNA. As a result, we also demonstrated that 4-cholesten-3-one disrupts membrane rafts and cell migration capacity. Conclusion Our results show that 4-cholesten-3-one exerts promising antitumor activity by altering LXR-dependent lipid metabolism in breast cancer cells without increasing lipogenesis.

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“…Fluvastatin conjugated with human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) produces anti-proliferative action against human hepatoma cancer cells through a concomitant accumulation of cells in the pre-G phase and induction of caspase 3 cleavage [ 82 ]. Atorvastatin causes strong growth inhibition of epithelial- and mixed epithelial-mesenchymal cancer cells by inhibiting the protein prenylation pathway [ 83 ]. Rosuvastatin inhibits cell proliferation and spheroid formation without cytotoxicity in prostate cancer cells and inhibits the expression of EMT markers vimentin, and Zeb-1 [ 84 ].…”

Section: Statin As a Single Agent In The Suppression Of Cancer Cell Proliferation And The Induction Of Apoptosismentioning

confidence: 99%

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

Pun

Jeong

2021

Pharmaceuticals

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Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

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Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Cited by 22 publications

References 53 publications

Attempts to use statins in cancer therapy: An update

Attempts to use statins in cancer therapy: An update

4-cholesten-3-one decreases breast cancer cell viability and alters membrane raft-localized EGFR expression by reducing lipogenesis and enhancing LXR-dependent cholesterol transporters

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

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