Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice

Jiang, Siqi; Li, Jun; Dong, Fang; Yang, Jian; Liu, De Jun; Yang, Xiaobin; Wang, Yahui; Yang, Min; Fu, Xue; Zhang, Xiaoxin; Li, Qing; Pang, Xiu Feng; Huo, Yan; Li, Jiao; Zhang, Jun Feng; Lee, Ho‐Young; Lee, Su Jae; Qin, Wen; Gu, Jiafeng; Sun, Yong-Wei; Zhang, Zhi Gang

doi:10.1053/j.gastro.2017.03.008

Cited by 198 publications

(162 citation statements)

References 61 publications

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“…Secondly, the activation of AMPK-AKT signaling is universally known to induce mTOR signaling, demonstrating a possible mechanism for metabolic reprogramming of hepatocytes by IL-22. Thirdly, it has also been suggested that mTOR signaling activation potentiates glycolytic enzymes expression, likely HK-2, c-Myc [43]. Our findings therefore indicate a stream-lined mechanism for the molecular basis of the liver protective potentials of IL-22, where IL-22 leads to the induction of mTOR activation, causing the upregulation of glycolytic enzymes, as suggested in Fig.…”

Section: Discussionsupporting

confidence: 68%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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AbstractInterleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights.

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Section: Discussionsupporting

confidence: 68%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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“…Western blot analysis was performed as described previously [35][36][37] . Anti-PIK3R5, N-cadherin, E-cadherin, Vimentin, MMP2, Beclin1, p62, ATG5, LC3-II, Bax, Bcl2, cleaved caspase-3, and GAPDH were purchased from Abcam (Cambridge, UK), and anti-p-AKT, AKT, p-mTOR, and mTOR were obtained from Cell Signaling Technology.…”

Section: Western Blotmentioning

confidence: 99%

miR-210-5p promotes epithelial–mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells

et al. 2020

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Osteosarcoma (OS) is a malignant bone tumor which occurs mainly in adolescents with frequent pulmonary metastasis and a high mortality rate. Accumulating evidence has indicated that microRNAs (miRNAs) play a vital role in various tumors by modulating target genes as well as signal pathways, and aberrant expression of miRNAs may contribute to OS progression. This study aimed to determine the association between miR-210-5p expression and OS progression and to investigate its potential underlying mechanism. Using reverse transcription-polymerase chain reaction (RT-PCR), miR-210-5p was found to be upregulated in clinical OS specimens and cell lines. Further functional analysis demonstrated that miR-210-5p promoted epithelial-mesenchymal transition (EMT) and induced oncogenic autophagy. Luciferase reporter assay, RNA-ChIP, and western blot analysis confirmed that PIK3R5, an essential regulator in the AKT/mTOR signaling pathway, is a target downstream gene of miR-210-5p. Overexpression or knockdown of PIK3R5 reversed the functional role of overexpression or knockdown of miR-210-5p, respectively. Silencing autophagyrelated gene 5 (ATG5) abolished the functional effects of miR-210-5p upregulation or PIK3R5 knockdown in OS cells. In vivo, miR-210-5p overexpression promoted OS tumor growth and pulmonary metastasis. Taken together, our results demonstrated that miR-210-5p promoted EMT and oncogenic autophagy by suppressing the expression of PIK3R5 and regulating the AKT/mTOR signaling pathway. Therefore, inhibition of miR-210-5p may represent a promising treatment for OS.

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“…Serotonin and 5-HTR2A agonists were found to induce melanogenesis in melanoma cell lines [9]. Jiang et al reported increased levels of serotonin and 5-HTR2B in human pancreatic ductal adenocarcinomas which promoted pancreatic tumor growth in mice [37]. Many other studies have similarly reported growth stimulatory effects of serotonin signaling through various 5-HTRs and inhibitory effects of 5-HTR antagonists in many tumor types [38,39].…”

Section: Discussionmentioning

confidence: 98%

“…However, there have also been reports, albeit much fewer, suggesting that treatment with serotonin agonists might also have anti-cancer effects in glioma [40] and breast cancer cells [41]. Involvement within the autocrine loops and activation of the MAPK, JNK, PI3K/Akt/mTOR [37,38] pathways has been implicated in serotonin's mitogenic role.…”

Section: Discussionmentioning

confidence: 99%

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

Liu

Stachura

et al. 2020

J Exp Clin Cancer Res

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Background: New therapies are urgently needed in melanoma particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors.Methods: Drug screening, IC50 determinations as well as synergy assays were detected by the MTT assay. Apoptosis using Annexin V and 7AAD staining was assessed using flow cytometry. TUNEL staining was performed using immunocytochemistry. Changes in phosphorylation of key molecules in PI3K/Akt/mTOR and other relevant pathways were detected by western blot as well as immunocytochemistry. To assess in vivo anti-tumor activity of Tegaserod, syngeneic intravenous and subcutaneous melanoma xenografts were used. Immunocytochemical staining was performed to detect expression of active Caspase-3, cleaved Caspase 8 and p-S6 in tumors. Evaluation of immune infiltrates was carried out by flow cytometry.Results: Using a screen of 770 pharmacologically active and/or FDA approved drugs, we identified Tegaserod (Zelnorm, Zelmac) as a compound with novel anti-cancer activity which induced apoptosis in murine and human malignant melanoma cell lines. Tegaserod (TM) is a serotonin receptor 4 agonist (HTR4) used in the treatment of irritable bowel syndrome (IBS). TM's anti-melanoma apoptosis-inducing effects were uncoupled from serotonin signaling and attributed to PI3K/Akt/mTOR signaling inhibition. Specifically, TM blunted S6 phosphorylation in both BRAF V600E and BRAF wildtype (WT) melanoma cell lines. TM decreased tumor growth and metastases as well as increased survival in an in vivo syngeneic immune-competent model. In vivo, TM also caused tumor cell apoptosis, blunted PI3K/Akt/mTOR signaling and decreased S6 phosphorylation. Furthermore TM decreased the infiltration of immune suppressive regulatory CD4 + CD25 + T cells and FOXP3 and ROR-γt positive CD4 + T cells. Importantly, TM synergized with Vemurafenib, the standard of care drug used in patients with late stage disease harboring the BRAF V600E mutation and could be additively or synergistically combined with Cobimetinib in both BRAF V600E and BRAF WT melanoma cell lines in inducing anti-cancer effects.

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Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice

Cited by 198 publications

References 61 publications

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

miR-210-5p promotes epithelial–mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

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