ArticleOncogene2017
Pyruvate dehydrogenase kinase 4 exhibits a novel role in the activation of mutant KRAS, regulating cell growth in lung and colorectal tumour cells.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).Cell communication and signaling : CCS · 2026Review
- PDK4 as a tumor suppressor in gastric cancer: implications for metabolic regulation, immune modulation, and prognostic potential.Discover oncology · 2025Article
- Novel Dichloroacetophenone-Based PDHK1 Inhibitors as Potent Anticancer Agents.Drug design, development and therapy · 2024Article
- Article
- Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2023Article
- Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.International journal of oncology · 2022Article
- Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis.International journal of oncology · 2021Article
- Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications.Bioscience reports · 2021Review
- Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxicTheranostics · 2021Article
- Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients.Journal of experimental & clinical cancer research : CR · 2020Article
- Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling in ovarian cancer.British journal of cancer · 2020Article
- Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase.International journal of cancer · 2019Review
- Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis.Liver research (Beijing, China) · 2018Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
RAS signalling is involved in the control of several metabolic pathways including glycolysis, mitochondrial respiration and glutamine metabolism. Importantly, we have found here that loss of PDHK4, a key regulator of the pyruvate dehydrogenase complex, caused a profound cell growth inhibition in tumour cells harbouring KRAS mutations. Using isogenic cells and a panel of colorectal and lung cell lines we demonstrated that KRAS mutant cells showed a dependency on PDHK4 whereas KRAS wild-type cells were significantly resistant to PDHK4 knockdown. We have found that PDHK4 plays a role in the post-translational regulation of mutant KRAS activity. Depletion of PDHK4 causes disruption of KRAS cellular localization, a reduction in KRAS activity which, in turn, results in reduced MAPK signalling. Interestingly, PDHK4 and KRAS depletion resulted in a similar metabolic phenotype consisting of a reduction of glucose and fatty acid oxidation. Moreover, stable expression of PDHK4 increased localization of activated KRAS at the plasma membrane and induced tumour cell growth in vitro and in vivo. Taken together these data support a model where PDHK4 regulates KRAS signalling and its tumorigenic properties and suggest that inhibition of PDHK4 could represent a novel therapeutic strategy to target KRAS mutant colorectal and lung cancers.
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