Emodin and rhein decrease levels of hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells

Hu, Lijuan; Cui, Rui; Liu, Hongyi; Wang, Feng

doi:10.18632/oncotarget.21330

Cited by 39 publications

(58 citation statements)

References 38 publications

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“…Rhein is a lipophilic anthraquinone mainly extracted from rhizomes of several traditional medicinal plants (12). A previous study revealed that rhein decreased the level of HIF-1α (a subunit of HIF-1) in tumor cells under hypoxic conditions (13). The present study identified correlations between HIF-1α and the immunosuppressive molecules in tissue samples from patients with CRC.…”

Section: Introductionsupporting

confidence: 58%

“…Since the expression of HIF-1α is inhibited by rhein (13), it may be hypothesized that rhein downregulates immunosuppressive molecules driven by HIF-1 and further enhances the anti-tumor effect of PBLs in hypoxia. The present study investigated the correlation between the mRNA levels of HIF-1α and the six immunosuppressive molecules in tumor tissue samples from patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

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Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions

et al. 2018

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The immunosuppressive tumor microenvironment limits the application of adoptive immunotherapy for solid tumors. Hypoxia is closely associated with the formation of the immunosuppressive tumor microenvironment. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-sensitive transcriptional activator that drives the transcription of several immunosuppressive molecules. In addition, previous studies confirmed that rhein downregulated the expression of HIF-1α, a subunit of HIF-1, in pancreatic cancer cells. The present study established correlations between mRNA expression levels of HIF-1α and six immunosuppressive molecules in colorectal cancer (CRC) tissue samples. This study examined the effect of rhein on the expression levels of HIF-1α and six immunosuppressive molecules in CRC cell lines under hypoxic conditions by western blot analysis and reverse transcription-quantitative polymerase chain reaction. This study demonstrated that rhein downregulated the expression of HIF-1α and immunosuppressive molecules in CRC cells under hypoxic conditions. In addition, the present study analyzed the cytotoxicity of peripheral blood lymphocytes in vitro using a non-toxic cytotoxicity assay. This study demonstrated that in vitro, rhein enhanced the cytotoxicity of effector lymphocytes toward tumor cells under hypoxic conditions, and therefore rhein may be used in combination with effector lymphocytes for the treatment of CRC.

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Section: Introductionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions

et al. 2018

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“…Data from the present study suggest that the Warburg effect in pancreatic cancer cells drives the pathogenesis of pancreatic cancer-induced cachexia. Inhibiting the Warburg effect in pancreatic cancer cells may attenuate the cachexia induced by pancreatic cancer [ 13 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells

Wang

Liu

et al. 2018

BMC Cancer

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BackgroundCancer cachexia is a cancer-induced metabolic disorder and a major cause of cancer-induced death. The constituents of cancer cachexia include an increase in energy expenditure, hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis and a decrease in body weight. The aetiology of cancer cachexia is unclear and may involve cancer-cell metabolism and secretion. In this study, we investigated whether the high glycolysis in cancer cells (the Warburg effect) triggers cachexia in athymic mice carrying pancreatic cancer cells.MethodsFirst, we examined five human pancreatic cancer cell lines for glycolysis and cachectic-cytokine secretion. Consequently, MiaPaCa2 and AsPC1 cells were selected for the present study, because the glycolysis in MiaPaCa2 cells was typically high and that in AsPC1 cells was exceptionally low. In addition, both MiaPaCa2 and AsPC1 cells were competent in the secretion of examined cytokines. Next, we transplanted MiaPaCa2 and AsPC1 cells subcutaneously in different athymic mice for 8 weeks, using intact athymic mice for control. In another experiment, we treated normal mice with the supernatants of MiaPaCa2 or AsPC1 cells for 7 days, using vehicle-treated mice for control. In both models, we measured food intake and body weight, assayed plasma glucose, triglycerides, and TNF-α and used Western blot to determine the proteins that regulated hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis in the corresponding tissues. We also studied the effect of MiaPaCa2-cell supernatants on the proteolysis of C2C12 skeletal-muscle cells in vitro.ResultsThe athymic mice carrying high-glycolytic MiaPaCa2 cells had anorexia and also showed evidence for cachexia, including increased hepatic gluconeogenesis, fat lipolysis and skeletal-muscle proteolysis and decreased body weight. The athymic mice carrying low-glycolytic AsPC1 cells had anorexia but did not show the above-mentioned evidence for cachexia. When normal mice were treated with the supernatants of MiaPaCa2 or AsPC1 cells, their energy homeostasis was largely normal. Thus, the cachexia in the athymic mice carrying MiaPaCa2 cells may not result from humeral factors released by the cancer cells. In vitro, MiaPaCa2-cell supernatants did not induce proteolysis in C2C12 cells.ConclusionThe Warburg effect in pancreatic cancer cells is an independent aetiological factor for pancreatic cancer-induced cachexia.

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“…The anti-tumor drug emodin has been shown to affect many different tumor cell lines and inhibit the growth of leukemia, breast cancer, colon cancer and lung cancer cells, etc ( 31 – 34 ). Moreover, although studies have indicated the anti-cancer effect of emodin on pancreatic carcinoma ( 35 , 36 ), the mechanism of action of emodin in inhibiting the development of pancreatic cancer remains incompletely elucidated. Therefore, we conducted the current study.…”

Section: Discussionmentioning

confidence: 99%

Emodin inhibits pancreatic cancer EMT and invasion by up‑regulating microRNA‑1271

Wang

Zhang

et al. 2018

Mol Med Report

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Emodin has a direct inhibitory effect on the growth and metastasis of a variety of malignant tumor cells. MicroRNA-1271 (miR-1271) has an extensive tumor-suppression effect by inhibiting epithelial mesenchymal transition (EMT) in tumor cells and induces tumor cell apoptosis. Proceeding with the EMT regulatory mechanism of pancreatic carcinoma, the present study aimed to examine the inhibitory effect of miR-1271 and emodin against invasion and metastasis of pancreatic carcinoma. The expression of EMT-related markers (E-cadherin, ZEB1 and TWIST1) was analyzed by western blotting. mRNA levels of miR-1271, E-cadherin, ZEB1 and TWIST1 in pancreatic tumor cells (SW1990) were measured through reverse transcription-quantitative polymerase chain reaction and cell invasiveness was detected using Transwell assays. In addition, a liver metastatic model was established with an implantation of pancreatic tumor tissue into the spleens of nude mice to study the effect of emodin on pancreatic cancer liver metastasis. In the present study, it was demonstrated that miR-1271 significantly decreased in pancreatic cancer cells and tissues. Twist1 may be a target gene of miR-1271. Emodin could inhibit the proliferation ability of pancreatic cancer cells and increased miR-1271 expression level. Further, we found that miR-1271 significantly inhibited SW1990 cell EMT and invasive ability. We also provided the evidence that emodin inhibited SW1990 cell EMT by raising the level of miR-1271. Moreover, the in vivo experiments have verified the inhibiting effect of emodin against liver metastasis of pancreatic cancer. The data in the present study indicated that emodin inhibited pancreatic cancer EMT and invasion by increasing the content of miR-1271.

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Emodin and rhein decrease levels of hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells

Cited by 39 publications

References 38 publications

Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions

Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions

The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells

Emodin inhibits pancreatic cancer EMT and invasion by up‑regulating microRNA‑1271

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