&lt;p&gt;Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells&lt;/p&gt;

Deng, Jun‐Li; Zhang, Rui; Zeng, Ying; Guo, Wei

doi:10.2147/cmar.s212643

Cited by 31 publications

(26 citation statements)

References 46 publications

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“…In PCa xenograft mice models, simvastatin treatment at 25 μM inhibited serum-induced Akt activity, cell migration and colony formation ( 150 ). Both simvastatin and fluvastatin inhibit cell proliferation and induce apoptosis in a dose- and time-dependent manner via the downregulation of Akt/Foxo1 phosphorylation in PCa ( 151 ). Simvastatin treatment also overcomes enzalutamide-induced resistance through the inhibition of mTOR-mediated AR degradation ( 102 ).…”

Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

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Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

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Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

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“…FOXO1 belongs to the FOXO family of transcription factors (FoxOs). The major types of malignant tumors show FOXO1 inactivation by hyperactivation of PI3K/Akt signaling [ 34 ]. FOXO1 has tight association with death-receptor-mediated apoptosis, and Akt directly inactivates FOXO1, downregulating FOXO1-controlled proteins, which are closely related to cell apoptosis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

FUT4siRNA augments the chemosensitivity of non-small cell lung cancer to cisplatin through activation of FOXO1-induced apoptosis

Gao

Liang

et al. 2020

BMC Cancer

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Background Increased fucosylation is associated with the chemoresistance phenotype. Meanwhile, fucosyltransferase IV (FUT4) amounts are frequently elevated in lung cancer and may be related to increased chemoresistance. Methods In the present work, FUT4’s role in cisplatin-induced apoptosis was assessed in A549 and H1975 cells, respectively. To clarify whether the FUT4 gene attenuates chemosensitivity in tumor cells, we constructed FUT4siRNA and evaluated its effects on cisplatin-induced apoptosis and cell growth inhibition. Cell viability, apoptosis, migration and invasion assay were conducted to investigate cisplatin sensitivity. The activation of EGFR/AKT/FOXO1 signaling were measured by western blot. The translocation of FOXO1 was assessed by IFC using Laser Scanning Confocal Microscope. Results We found that FUT4 knockdown dose-dependently increased cisplatin-associated cytotoxicity. Furthermore, FUT4 silencing induced apoptosis and inhibited proliferation in A549 and H1975 cells by suppressing Akt and FOXO1 phosphorylation induced by cisplatin administration, which resulted in nuclear translocation of FOXO1. Conclusion These results suggested FUT4 might control chemoresistance to cisplatin in lung cancer by suppressing FOXO1-induced apoptosis.

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“…The growth-inhibitory properties of fluvastatin have been reported to be due to increased cell death in cell lines and mouse models [23][24][25]. To determine whether increased apoptotic cell death was indeed responsible for reduction in tumor growth in fluvastatin-treated mice, we performed TUNEL staining on a set of mammary glands (n = 8 samples per group) at the end of the 16-week treatment.…”

Section: Fluvastatin Inhibits Mammary Tumor Growth Through Induction Of Apoptosismentioning

confidence: 99%

Efficacy of fluvastatin and aspirin for prevention of hormonally insensitive breast cancer

Bhardwaj

Embury

Rojo

et al. 2021

Breast Cancer Res Treat

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Purpose Primary prevention of hormonally insensitive breast cancers remains an important clinical need and repurposing existing low-toxicity drugs represents a low-cost, efficient strategy for meeting this goal. This study targeted the cholesterol pathway using fluvastatin, a cholesterol-lowering drug, and aspirin, an AMPK activator that acts as a brake in the cholesterol pathway, in a transgenic mouse model of triple-negative breast cancer (TNBC). Methods Using SV40C3 TAg mice, the efficacy and mechanism of fluvastatin, aspirin, or both in combination were compared with vehicle alone. Results Sixteen-weeks of fluvastatin treatment resulted in significant delay in onset of tumors (20 weeks vs. 16.8 weeks in vehicle treatment, p = 0.01) and inhibited tumor incidence and tumor multiplicity by 50% relative to the vehicle control. In animals that developed tumors, fluvastatin treatment inhibited tumor weight by 75% relative to vehicle control. Aspirin alone did not significantly affect tumor latency, tumor incidence or tumor burden compared to vehicle control. Fluvastatin and aspirin in combination delayed the onset of tumors but failed to inhibit tumor incidence and tumor multiplicity. The growth-inhibitory effects of fluvastatin were mediated through increased FAS/FASL mediated apoptotic cell death that was characterized by increased cleaved PARP and driven in part by depletion of an isoprenoid, geranyl geranyl pyrophosphate (GGPP). Conclusions In line with NCI’s emphasis to repurpose low-toxicity drugs for prevention of cancer, fluvastatin was effective for prevention of TNBC and warrants further clinical testing. Aspirin did not provide chemopreventive benefit.

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<p>Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells</p>

Cited by 31 publications

References 46 publications

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

FUT4siRNA augments the chemosensitivity of non-small cell lung cancer to cisplatin through activation of FOXO1-induced apoptosis

Efficacy of fluvastatin and aspirin for prevention of hormonally insensitive breast cancer

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