FOXO3 Growth Inhibition of Colonic Cells Is Dependent on Intraepithelial Lipid Droplet Density

Qi, Wentao; Fitchev, Philip; Cornwell, Mona; Greenberg, Jordan; Cabe, Maleen; Weber, Christopher R.; Roy, Hemant K.; Crawford, Susan E.; Savkovic, Suzana D.

doi:10.1074/jbc.m113.470617

Cited by 53 publications

(64 citation statements)

References 53 publications

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“…In our system, DHA stimulated SIRT6 activation (Figure 2A, B), which resulted in apoptosis ( Figure 3A, B). This observation is supported by previous reports, which showed that SIRT6 decreases transcriptional activity at forkhead box O3 (FOXO3a) and c-Jun promoters, which regulate genes such as AKT and GSK-3β, promoting apoptotic cell death [34,35]. It is possible that the mechanism for DHA-induced apoptosis involves FOXO3a or c-Jun.…”

Section: Discussionsupporting

confidence: 86%

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Jeong¹,

Jing²,

Shin³

et al. 2017

Preprint

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Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was

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Section: Discussionsupporting

confidence: 86%

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Jeong¹,

Jing²,

Shin³

et al. 2017

Preprint

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“…This is reminiscent of the "sibling rivalry" between HIF1α and HIF2α documented across various ccRCC models ( 7 ). Similar results were seen in a mouse colon tumor model, where tumor proliferation was PLIN2-and lipid droplet-dependent, whereas the HIF1α target FOXO3 induced tumor death and PLIN2 and lipid depletion ( 8 ). However, interactions between HIF isoforms are often cell type specifi c. PLIN2 is HIF1α dependent but not HIF2α dependent in glioblastoma and breast cancer cell lines ( 3 ).…”

supporting

confidence: 63%

Through a Clear Cell, Darkly: HIF2α/PLIN2–Maintained Fat Droplets Protect ccRCCs from ER Stress

Sim

Johnson

2015

Cancer Discovery

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Summary: Qiu and colleagues describe how a structural component of lipid droplets is markedly induced in pseudohypoxic renal tumors, where it maintains endoplasmic reticulum (ER) homeostasis. This adaptation is indispensable in tumor cells-where growth demands and a fl uctuating blood supply place unnatural stresses on ER function-and is therefore an attractive therapeutic target. Cancer Discov; 5(6); 584-5. ©2015 AACR.See related article by Qiu and colleagues, p. 652 (2).With their lethal cocktail of high metabolic demands and poor vascularization, solid tumors are regularly assailed by hypoxia and endoplasmic reticulum (ER) stress. These insults compound each other-because protein folding consumes oxygen and energy, a hypoxic cell is particularly susceptible to ER stress. Healthy cells have evolved dedicated response pathways for each insult; these favor adaptation where possible, but lead to cell death when inappropriately activated. The unfolded protein response (UPR) alleviates ER stress by inhibiting translation, expediting protein processing, ERassociated degradation, and autophagy. The hypoxic response aims to match oxygen supply to demand and is primarily mediated by transcription factors known as hypoxia-inducible factors (HIF; the most important isoforms being HIF1α and HIF2α). When oxygen is low, HIF availability increases dramatically because it is no longer targeted for degradation by a complex that includes the von Hippel-Lindau protein (VHL).Clear-cell renal cell carcinomas (ccRCC) can arise from loss-of-function mutations of VHL -these tumors overexpress HIF, i.e., they are pseudohypoxic. The term "clear cell" alludes to the abundance of cytosolic lipid droplets in these tumors. Lipid accumulation is unsurprising, given that HIF suppresses lipolysis and β-oxidation of fatty acids while conserving energy stores in preparation for reoxygenation. However, lipid droplets have another less-recognized function-they can alleviate ER stress by sequestering toxic lipids in neutral forms and providing an ER-associated route to retrotranslocate soluble misfolded proteins ( 1 ). The current work by Qiu and colleagues ( 2 ) describes the novel convergence of HIF and ER stress response signals on lipid droplets in ccRCC.PLIN2 is a lipid droplet-associated structural protein with well-described metabolic functions. In the current study, Qiu and colleagues fi rst noted from ccRCC tissue samples that PLIN2 expression increases specifi cally with HIF2α expression. They went on to show that this relationship was causal, because PLIN2 levels declined as a result of HIF2α knockdown in the 786-O and RCC4 cell lines. Furthermore, this relationship was pathologically signifi cant. HIF2α knockdown in 786-O cells slowed xenograft growth and depleted lipid stores, but both neutral lipid staining and tumorigenicity were restored by PLIN2 overexpression. PLIN2 loss sensitizes ccRCC cultures to oleic acid treatment and pharmacologic agents that induce proteotoxicity. Conversely, inhibition of the UPR, mTORC1, and protein syn...

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“…Fatty acid treatment also induces DGAT2 to associate with LD and take part in LD expansion (Harris et al, 2011; Jin et al, 2014; McFie et al, 2014; Wilfling et al, 2013; Xu et al, 2012). In addition to TG storage and control of energy metabolism, LD are involved in cancer cachexia and cancer cell growth (Qi et al, 2013; Yue et al, 2014). We now can add acylceramide to this group of storage lipids, and suggest that hydrolysis of acylceramide at its ester link by lipases may constitute a source of ceramide generation.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

et al. 2017

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SUMMARY In an approach aimed at defining interacting partners of ceramide synthases (CerS), we found that fatty acyl CoA synthase ACSL5 interacts with all CerS. We demonstrate that ACSL5 generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LD in cells and in livers of mice on a high fat diet. The study also implicates this novel pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms.

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FOXO3 Growth Inhibition of Colonic Cells Is Dependent on Intraepithelial Lipid Droplet Density

Cited by 53 publications

References 53 publications

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Through a Clear Cell, Darkly: HIF2α/PLIN2–Maintained Fat Droplets Protect ccRCCs from ER Stress

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

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