The effect of HIF-1&amp;alpha; and PKM1 expression on acquisition of chemoresistance

Okazaki, Mitsuyoshi; Fushida, Sachio; Tsukada, Tomoya; Koyama, Jun; Oyama, Katsunobu; Miyashita, Tomoharu; Ninomiya, Itasu; Harada, Shinichi; Ohta, Tetsuo

doi:10.2147/cmar.s166136

Cited by 22 publications

(13 citation statements)

References 41 publications

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“…Previous studies indicated that HIF-1a is an important regulator of chemoresistance. [14][15][16][17] Our data also showed that the mRNA and protein expression of HIF-1a in Dox resistant was significantly greater than that in parental cells (Figure S2).…”

Section: Upregulation Of Pdk4 Was Essential For Dox Resistance Of Cervical Cancer Cellssupporting

confidence: 57%

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer

Zhao

Wang

et al. 2020

Molecular Therapy - Oncolytics

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Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, investigation about molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The molecular mechanisms responsible for the chemoresistance of cervical cancer were investigated by the use of doxorubicin (Dox)-resistant HeLa/Dox and SiHa/Dox cells. Our data showed that chemoresistant cells exhibited significantly higher glucose consumption, lactate production rate, and ATP levels than that of their parental cells. Among metabolic and glycolytic related genes, the expression of PDK4 was upregulated in Dox-resistant cells. Knockdown of PDK4 can decrease glucose consumption, lactate production rate, and ATP levels and further sensitize resistant cervical cancer cells to Dox treatment. By screening microRNAs (miRNAs), which can regulate expression of PDK4, we found that miR-16-5p was downregulated in chemoresistant cells. Overexpression of miR-16-5p can decrease the expression of PDK4 and sensitize the resistant cells to Dox treatment. Xenograft models confirmed that knockdown of PDK4 can increase chemotherapy efficiency for in vivo tumor growth. Collectively, our data suggested that miR-16-5p/PDK4-mediated metabolic reprogramming is involved in chemoresistance of cervical cancer.

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Section: Upregulation Of Pdk4 Was Essential For Dox Resistance Of Cervical Cancer Cellssupporting

confidence: 57%

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer

Zhao

Wang

et al. 2020

Molecular Therapy - Oncolytics

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“…ET1 receptors regulate HIF1α, which can activate the transcription of the genes VEGF‐A and VEGF‐C . In our study, gastric cancer patients with high expression of ETAR also had upregulated VEGF expression, and the two were subsequently found to be positively correlated.…”

Section: Discussionsupporting

confidence: 49%

Endothelin‐A receptor in gastric cancer and enhanced antitumor activity of trastuzumab in combination with the endothelin‐A receptor antagonist ZD4054

Shen

et al. 2019

Annals of the New York Academy of Sciences

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Endothelin‐A receptor (ETAR) is overexpressed in cancers and can function through transactivation of the epidermal growth factor receptor. We explored ETAR in gastric cancer and investigated the antitumor effect of trastuzumab in combination with the ETAR antagonist ZD4054. The expression of ETAR was significantly correlated with the expression of vascular endothelial growth factor. Univariate and multivariate analyses further showed that ETAR expression correlated with reduced survival in gastric cancer patients. In vitro, ZD4054 increased the antiproliferative effect of trastuzumab in gastric cancer cell lines. Moreover, the addition of ZD4054 to trastuzumab significantly increased apoptosis in gastric cancer cell lines. In vivo, tumor growth was considerably inhibited by treatment with ZD4054 and trastuzumab, and the tumor volume in the trastuzumab and ZD4054 combination group was smaller than in the other groups. The detection of ETAR could help predict the prognosis of gastric cancer patients. Additionally, this study provides support for the therapeutic use of the combination of ZD4054 and trastuzumab as an anticancer treatment, especially for gastric cancer.

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“…Activation of the PI3K/AKT signaling pathway inhibits high blood glucose-induced apoptosis and senescence in nucleus pulposus cells 33 . PKM1/2 is involved in glycolysis, which is closely related to the occurrence of diabetes 34,35 . GLUT4 is a glucose carrier/transporter located on the cell membrane 36 .…”

Section: Discussionmentioning

confidence: 99%

Gynura divaricata exerts hypoglycemic effects by regulating the PI3K/AKT signaling pathway and fatty acid metabolism signaling pathway

Wang

et al. 2020

Nutr. Diabetes

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Objectives: The study aimed to examine the anti-diabetic effects of Gynura divaricata (GD) and the underlying mechanism. Methods: Information about the chemical compositions of GD was obtained from extensive literature reports. Potential target genes were predicted using PharmMapper and analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). To validate the results from bioinformatics analyses, an aqueous extract of GD was administered to type 2 diabetic rats established by feeding a high-fat and high-sugar diet followed by STZ injection. Key proteins of the PI3K/AKT signaling pathway and fatty acid metabolism signaling pathway were investigated by immunoblotting. Results: The blood glucose of the rats in the GD treatment group was significantly reduced compared with the model group without treatment. GD also showed activities in reducing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (CREA). The levels of urine sugar (U-GLU) and urine creatinine (U-CREA) were also lowered after treatment with GD. Bioinformatics analysis showed that some pathways including metabolic pathways, insulin resistance, insulin signaling pathway, PPAR signaling pathway, bile secretion, purine metabolism, etc. may be regulated by GD. Furthermore, GD significantly increased the protein expression levels of PKM1/2, p-AKT, PI3K p85, and GLUT4 in the rat liver. In addition, the expression levels of key proteins in the fatty acid metabolism signaling pathway including AMPK, p-AMPK, PPARα, and CPT1α were significantly upregulated. The antiapoptotic protein BCL-2/BAX expression ratio in rats was significantly upregulated after GD intervention. These results were consistent with the bioinformatics analysis results. Conclusions: Our study suggests that GD can exert hypoglycemic effects in vivo by regulating the genes at the key nodes of the PI3K/AKT signaling pathway and fatty acid metabolism signaling pathway.

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The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance

Cited by 22 publications

References 41 publications

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer

Endothelin‐A receptor in gastric cancer and enhanced antitumor activity of trastuzumab in combination with the endothelin‐A receptor antagonist ZD4054

Gynura divaricata exerts hypoglycemic effects by regulating the PI3K/AKT signaling pathway and fatty acid metabolism signaling pathway

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