Inhibition of pyruvate dehydrogenase kinase‑1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming

Xu, Huadan; He, Yichun; Ma, Jiaoyan; Zhao, Yuanxin; Liu, Yanan; Sun, Liankun; Su, Jing

doi:10.3892/ijo.2020.5098

Cited by 6 publications

(5 citation statements)

References 41 publications

(55 reference statements)

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“…Recent research has indicated that PDK1 contributes to chemotherapy resistance [ 32 , 33 ]. However, the role of miR-148a/PDK1 for therapeutic effects in breast cancer is unclear.…”

Section: Resultsmentioning

confidence: 99%

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance

Xie

Shi

Qian

et al. 2022

Cancers

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Background: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. Methods: Gene set enrichment analysis (GSEA) and Pearson’s correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. Results: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a—including miR-148a’s ability to increase cell sensitivity to Adriamycin (ADR) treatment—inhibiting cell glycolysis, invasion and epithelial–mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. Conclusion: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future.

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“…Recent research has indicated that PDK1 contributes to chemotherapy resistance [ 32 , 33 ]. However, the role of miR-148a/PDK1 for therapeutic effects in breast cancer is unclear.…”

Section: Resultsmentioning

confidence: 99%

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance

Xie

Shi

Qian

et al. 2022

Cancers

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“…The activity of pyruvate dehydrogenase is inhibited due to the highly expressed pyruvate dehydrogenase kinase 1 in HCC [ 39 ]. Inhibition of pyruvate dehydrogenase kinase 1 using a small molecule, dicoumarol, increased the OXPHOS flux in HCC, which can enhance the sensitivity of oxaliplatin for HCC chemotherapy [ 40 ]. SCT‐1015 provided the dual controlling point in metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

et al. 2022

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Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)‐approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT‐1015, that allosterically activated adenosine monophosphate‐activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT‐1015 was shown to bind the AMPK α and β‐subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT‐1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo . We further found that AMPK formed protein complexes with hypoxia‐inducible factor 1‐alpha (HIF1α) and that SCT‐1015‐activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin‐proteasome system. With declined HIF1α abundance, many glycolysis‐related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT‐1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT‐1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC.

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“… 65 However, HCC cells reprogram themselves, where pyruvate dehydrogenase kinase 1 (PDK1) is upregulated and activated, which inactivates PDH, suppressing the TCA cycle and shifting glucose metabolism towards glycolysis. 66 , 67 Another important factor involved in the fate of pyruvate in HCC is the mitochondrial pyruvate carrier (MPC) responsible for the pyruvate transport into the mitochondria for the oxidative phase of cellular respiration. 68 Downregulation of the MPC complex in HCC has been observed, thus inhibiting pyruvate transport to mitochondria and shifting glucometabolism to enhanced lactate production.…”

Section: Fate Of Pyruvate and Lactatementioning

confidence: 99%

Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma

Bhat,

Farooq,

Ismail

et al. 2023

Technol Cancer Res Treat

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Hepatocellular carcinoma (HCC) is the primary form of liver cancer. It causes ∼ 800 000 deaths per year, which is expected to increase due to increasing rates of obesity and metabolic dysfunction associated steatotic liver disease (MASLD). Current therapies include immune checkpoint inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies, but these therapies are not satisfactorily effective and often come with multiple side effects and recurrences. Metabolic reprogramming plays a significant role in HCC progression and is often conserved between tumor types. Thus, targeting rewired metabolic pathways could provide an attractive option for targeting tumor cells alone or in conjunction with existing treatments. Therefore, there is an urgent need to identify novel targets involved in cancer-mediated metabolic reprogramming in HCC. In this review, we provide an overview of molecular rewiring and metabolic reprogramming of glucose metabolism in HCC to understand better the concepts that might widen the therapeutic window against this deadly cancer.

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Inhibition of pyruvate dehydrogenase kinase‑1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming

Cited by 6 publications

References 41 publications

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance

A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma

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