A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program

Giudetti, Anna Maria; Domenico, Stefania De; Ragusa, Andrea; Lunetti, Paola; Gaballo, Antonio; Franck, Julien; Simeone, Pasquale; Nicolardi, Giuseppe; Nuccio, Francesco De; Santino, Angelo; Capobianco, Loredana; Lanuti, Paola; Fournier, Isabelle; Salzet, Michel; Maffia, Michele; Vergara, Daniele

doi:10.1016/j.bbalip.2018.12.011

Cited by 72 publications

(65 citation statements)

References 41 publications

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“…Our results complement previous findings that implicate HGF-Met in the cell wound response and migratory behavior of the RPE, phenomena that are linked to EMT (18)(19)(20). EMT has been well characterized in systems-based examinations of other tissues and cell types (21)(22)(23)(24)(25), and targetbased analyses of EMT have been conducted in RPE (26)(27)(28)(29), but to date EMT has not been thoroughly characterized in RPE. It is our hope that our findings provide a useful resource for future study of a variety of RPE diseases.…”

Section: Introductionsupporting

confidence: 87%

Proteomic and phosphoproteomic analysis identifies novel liver-related signaling in retinal pigment epithelial cells during epithelial-mesenchymal transition

Mertz

Sripathi

Yang

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is associated with several potentially blinding retinal diseases. Proteomic and phosphoproteomic studies were performed on human pluripotent stem cell-derived RPE (hPSC-RPE) monolayers to better understand the pathways mediating RPE EMT. EMT was induced by enzymatic dissociation or by co-treatment with transforming growth factor beta (TGFβ) and tumor necrosis factor alpha (TNFα; TGNF). The global and phosphoproteomes were analyzed at 1 hr post EMT induction to capture early events in kinase/phosphatase signaling cascades and at 12 hrs to define early changes in protein abundance. Pathway enrichment analysis revealed that TGNF and Dissociation rapidly perturbed signaling in many of the same pathways, with striking similarity in the phosphoproteome at 1 hr. Surprisingly, functions related to liver cell proliferation and hyperplasia were strongly enriched in the phosphosites altered by both treatments at 1 hr and in protein abundance changes at 12 hrs. Hepatocyte Growth Factor-cMET signaling exhibited the strongest overall enrichment in both treatments. These signaling pathways may serve as suitable targets for the development of therapeutic strategies for the inhibition of RPE EMT, and thus progression of several debilitating visual diseases.

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Section: Introductionsupporting

confidence: 87%

Proteomic and phosphoproteomic analysis identifies novel liver-related signaling in retinal pigment epithelial cells during epithelial-mesenchymal transition

Mertz

Sripathi

Yang

et al. 2020

Preprint

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“…SREBP1 is a critical transcription factor that controls the expression of genes important for the uptake and synthesis of lipids, such as cholesterol, fatty acids, and phospholipids [32]. Accumulating evidence suggests that SREBP1 facilitates tumor progression, and the upregulation of SREBP1 has often been detected in many cancer types [22][23][24][25][26][27][33][34][35][36]. In this study, we first identified an increased SREBP1 expression in different ESCC cohorts, which was in an inverse relationship with tumor suppressor miR-142-5p.…”

Section: Discussionmentioning

confidence: 75%

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Huang

Hsu

et al. 2019

Cells

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Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Cells 2020, 9, 7 2 of 15Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

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“…There have been reports, however, suggesting that some cancers, including breast cancer, can oxidize ketone bodies and fatty acids for growth (162)(163)(164)(165). The uptake of ketone bodies or fatty acids together with oxygen consumption in tumor cells is not proof that the ketone bodies or fatty acids can be used to generate energy through OxPhos (34, 46,166). Indeed, Kuok et al recently showed that palmitate could increase oxygen consumption rate (OCR) by stimulating ATP usage and insulin secretion rather than by increasing beta-oxidation (167).…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

“…Indeed, Kuok et al recently showed that palmitate could increase oxygen consumption rate (OCR) by stimulating ATP usage and insulin secretion rather than by increasing beta-oxidation (167). Fatty acids are potent swelling and uncoupling agents that can stimulate insulin secretion and glucose/glutamine consumption thus making it appear as if tumor cells can metabolize fatty acids for energy (166,(168)(169)(170). In other words, fatty acids can stimulate utilization of glucose and glutamine.…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

“…In other words, fatty acids can stimulate utilization of glucose and glutamine. Many tumor cells including breast cancer cells will store fatty acids as lipid droplets (166,171,172). Lipid droplet storage is considered a protection mechanism from the lethal effects of saturated fatty acids in cells that cannot metabolize fats for energy (171)(172)(173)(174).…”

Section: Ketogenic Metabolic Therapymentioning

confidence: 99%

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Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

et al. 2020

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Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

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A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program

Cited by 72 publications

References 41 publications

Proteomic and phosphoproteomic analysis identifies novel liver-related signaling in retinal pigment epithelial cells during epithelial-mesenchymal transition

Proteomic and phosphoproteomic analysis identifies novel liver-related signaling in retinal pigment epithelial cells during epithelial-mesenchymal transition

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

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