CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway

Pan, Jingxue; Fan, Zhiyuan; Wang, Zhenqiang; Dai, Qinggang; Xiang, Zhen; Yuan, Fei; Yan, Min; Zhu, Zhenggang; Liu, Bingya; Li, Chen

doi:10.1186/s13046-019-1049-7

Cited by 169 publications

(159 citation statements)

References 38 publications

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“…Exogenous treatment of FABP4 increased Akt and MAPK signaling. The increased expression of the FA transporter CD36 in gastric cancer tissues also correlated with poor prognosis in patients [121]. CD36 mediates the palmitate acid-induced metastasis of GC via Akt.…”

Section: Lipid Metabolismmentioning

confidence: 88%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Section: Lipid Metabolismmentioning

confidence: 88%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

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“…Hua et al reported that knockdown of ANXA11 suppressed gastric cancer cell proliferation, invasion and migration through the AKT/GSK-3β pathway, which was acted as a prognostic factor and promising molecular target for gastric cancer treatment [31]. Pan et al demonstrated that CD36 regulated palpitate acid-induced metastasis in gastric cancer by AKT/GSK-3β/βcatenin pathway, acting as a potential molecular target for clinical intervention [32]. In our study, we found that miR-450 blocked the AKT/GSK-3β signaling pathway to regulate the progression of gastric cancer and miR-450 levels were related with strength of the AKT/GSK-3β signal pathway.…”

Section: Discussionmentioning

confidence: 99%

MiR-450 inhibits cell proliferation, migration and invasion and induces apoptosis in gastric cancer via targeting CREB1

Zhao¹,

Zhang²,

Y³

et al. 2020

Preprint

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Background：Gastric cancer seriously affects human health and research on gastric cancer is increasing. In recent years, molecular targets are hot research topics. We aimed to explore the effects and mechanisms of miR-450 on the development and progression of gastric cancer.Methods：We used gain-of-function approaches to investigate the gastric cancer cell proliferation, apoptosis, migration and invasion, including, RT-qPCR, CCK-8, colony formation, flow cytometry, western blot, wound healing, transwell chamber, HE, TUNEL, dual luciferase reporter and tumor formation analysis.Results：We found that the expression levels of miR-450 were greatly decreased in gastric cancer cells and overexpression of miR-450 inhibited the gastric cancer cell proliferation, migration and invasion, while induced apoptosis in gastric cancer in vitro. Moreover, we demonstrated that ectopic expression of miR-450 inhibited tumor growth in vivo. At the molecular level, overexpression of miR-450 significantly increased the expression levels of apoptosis-associated proteins, including Caspase-3, Caspase-9 and BAX, while inhibited the expression level of Bcl-2. Mechanically, luciferase reporter experiment suggested that CREB1 had a negative correlation with miR-450 expression and knockdown of CREB1 alleviated gastric cancer. Furthermore, we also found that miR-450 inhibited the activation of AKT/GSK-3β signaling pathway to inhibit the progression of gastric cancer.Conclusions：miR-450 repressed gastric cancer cell proliferation, migration and invasion and induced apoptosis through targeting CREB1 by modulating AKT/GSK-3β signaling pathway, which may provide a new molecular target for the treatment of gastric cancer.

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“…CD36 serves as the surface receptor for palmitate uptake and plays a critical role in palmitate-induced signaling pathways. It has been shown that increased CD36 expression in gastric cancer is correlated with poor prognosis [82]; accordingly, palmitate promotes gastric cancer metastasis in a CD36-dependent manner [83]. Palmitate stimulation increases monocytic CD36 expression, macrophage differentiation, and proinflammatory cytokine production [84].…”

Section: Involvement Of Palmitate In Immune-related Cell Interactionsmentioning

confidence: 99%

“…Since CD36 serves as the major transporter for cell palmitate uptake, the targeting of palmitate-mediated signaling has emerged as a potential therapeutic tactic. Indeed, palmitate-induced metastasis of gastric cancer is dependent on CD36, and high CD36 expression levels in gastric cancer patients correlate with poor clinical outcome; therefore, there is a possibility that blocking of the CD36-palmitate axis may serve as a potential gastric cancer treatment [83]. Indeed, CD36 deletion in a prostate cancer animal model revealed a dramatic decrease in fatty acid uptake and ameliorated cancer progression [86].…”

Section: Targeting Of Palmitate-induced Pathways As a Therapeutic Strmentioning

confidence: 99%

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

Tzeng

Chyuan

Chen

2019

Cells

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Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.Fatty acid β-oxidation is a major process that provides energy by degrading fatty acids. The enzymes responsible for fatty acid β-oxidation are mainly located in the mitochondria and peroxisomes. Each β-oxidation cycle can generate one acetyl-CoA molecule, which serves as the source for tricarboxylic acid cycle progression and yields more ATP per carbon than that from sugars by oxidative phosphorylation [7]. In contrast to the removal of two carbons from long-chain fatty acids in each β-oxidation round, fatty acid synthesis is catalyzed by joining two carbon units to the growing acyl chain via the cytosolic fatty acid synthase complex [8]. Palmitate is a 16-carbon saturated fatty acid produced via the fatty acid synthesis pathway in a fatty acid synthase-dependent manner, and acts as the major lipid mediator in inflammatory response regulation. Palmitic Acid-Regulated Innate Immune ResponsesCell uptake of palmitate is mainly mediated by the membrane fatty acid transporter CD36, also known as scavenger receptor B2 [9], although palmitate can also enter cells by other mechanisms, including direct membrane interactions, albumin-mediated transfer, and lipoprotein lipase-mediated uptake [10]. Accumulating evidence suggests a critical role by palmitic acid in modulating the activation of pattern recognition receptors in innate immune cells (Figure 1). Indeed, accumulating evidence reveals that although not through direct engagement of Toll-like receptors (TLRs), palmitate can modulate TLR downstream signaling in response to their ligand stimulation [11,12]. Palmitate is believed to be a TLR4 agonist that promotes macrophage activation and lipid metabolism-associated inflammation. Recently, however, it has been demonstrated that palmitate-induced inflammatory effects are not triggered by the direct binding of palmitate to TLR4, but through a combination of palmitate-mediated and TLR4-dependent priming, which alters cellular lipid metabolic pathways, gene expression, and membrane lipid composition, the prerequisite changes that are ...

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CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway

Cited by 169 publications

References 38 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

MiR-450 inhibits cell proliferation, migration and invasion and induces apoptosis in gastric cancer via targeting CREB1

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

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