Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer

Brovkovych, Viktor; Izhar, Yasir; Danes, Jeanne M.; Dubrovskyi, Oleskii; Sakallioglu, Isin T.; Morrow, Lauren M.; Atilla‐Gokcumen, G. Ekin; Frasor, Jonna

doi:10.1038/s41389-018-0076-0

Cited by 49 publications

(33 citation statements)

References 43 publications

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“…In this study, we found that fatostatin could exert a more obvious inhibitory effect on ER-positive breast cancer cells than ER-negative breast cancer cells, which was consistent with the results by Brovkovych et al 38 In addition, both Western blotting and immunohistochemistry staining demonstrated that fatostatin could significantly downregulate ER, which is worth exploring further. We wondered whether the deregulated ER resulted from the deregulation of protein synthesis or protein degradation.…”

Section: Discussionsupporting

confidence: 92%

<p>Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer</p>

Liu

Zhang

et al. 2020

DDDT

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Background: Tamoxifen is the cornerstone of adjuvant therapy for hormone receptorpositive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo. Methods: Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice. Results: The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen. Conclusion: Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.

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Section: Discussionsupporting

confidence: 92%

<p>Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer</p>

Liu

Zhang

et al. 2020

DDDT

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“…RNA was isolated and RT-QPCR performance as previously published [9] . Primer sequences are available upon request.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was isolated using Trizol according to the manufacturer's instructions (Ambion). RNA was isolated and RT‐QPCR performance as previously published . Primer sequences are available upon request.…”

Section: Methodsmentioning

confidence: 99%

Removal of Serum Lipids and Lipid‐Derived Metabolites to Investigate Breast Cancer Cell Biology

Brovkovych

Aldrich

et al. 2019

Proteomics

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The use of cultured cells has been instrumental in studying biochemical, molecular, and cellular processes. The composition of serum that cells are maintained in can have a profound impact on important cellular checkpoints. We have analyzed cell growth and apoptosis in an estrogen receptor positive breast cancer cell line in the presence of serum that have been treated to remove steroids or lipids, as well-described in the literature. We showed that maintaining cells in the presence of charcoal-dextran-treated serum causes reduced growth rate, which can be reversed by the addition of estradiol. Silica-treated-serum also slowed down cell growth and induced apoptosis. In order to investigate the role of lipids in these phenotypes, we investigated the levels of a wide range of lipids in different sera. We showed that silica-treatment significantly depletes phosphatidylcholines and cholesterol. We also show that lipogenesis is stimulated when cells are cultured with silica-treated-serum and this was reversed by the addition of exogenous lipids, which also restored growth rate and apoptosis. Our results show that cultured cells are sensitive to different serum, most likely due to the differences in levels of structural and signaling metabolites present in their growth environment.

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“…Although we cannot rule out the role of fatty acid biosynthesis, the data we present here suggest that phospholipid turnover might be involved, at least in part for the accumulation of PUFA‐TAGs. This turnover could be involved in sequestering polyunsaturated fatty acids into TAGs and lipid droplets and limit phospholipid‐induced membrane damage during apoptosis …”

Section: Resultsmentioning

confidence: 99%

The Role of p38 MAPK in Triacylglycerol Accumulation during Apoptosis

Saitou

Atilla‐Gokcumen

2019

Proteomics

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Lipids are emerging as key regulators of apoptosis. Specific lipid species are associated with apoptosis with important functional roles, but the understanding of the regulation of these lipid species is still limited. It has been previously shown by our laboratory that polyunsaturated triacylglycerols accumulate and get stored within lipid droplets during apoptosis via activated glycerolipid biosynthesis. In this work, the biochemical mechanisms that result in the activation of glycerolipid biosynthesis and, consequently, triacylglycerol and lipid droplet accumulation during apoptosis are investigated. The transcriptomes of control and apoptotic HCT‐116 cells are compared and gene enrichment analysis revealed the upregulation of p38 mitogen‐activated protein kinase (MAPK). It is shown that p38 MAPK regulates triacylglycerol biosynthesis through diacylglycerol acyltransferase1 during apoptosis. Perilipin 2 and cytosolic phospholipase A2delta are also shown to be involved in lipid droplet and polyunsaturated triacylglycerol accumulation in this process. Overall, the results provide new insights into the upregulation of glycerolipid synthesis during apoptosis.

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Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer

Cited by 49 publications

References 43 publications

<p>Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer</p>

<p>Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer</p>

Removal of Serum Lipids and Lipid‐Derived Metabolites to Investigate Breast Cancer Cell Biology

The Role of p38 MAPK in Triacylglycerol Accumulation during Apoptosis

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