Open Access

ARTICLE

Overexpression of Pyruvate Dehydrogenase E1a Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma

Jihong Sun^*†1, Jingjing Li^†1, Zhixian Guo^†, Lu Sun^†‡, Chenghui Juan^§, Yubing Zhou^¶, Hongli Gu^†, Yan Yu^†, Qiuyue Hu^†, Quancheng’ Kan^¶, Zujiang Yu^†

* Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
† Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
‡ Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
§ Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
¶ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

Oncology Research 2019, 27(4), 407-417. https://doi.org/10.3727/096504018X15180451872087

Abstract

Most cancers rely disproportionately on glycolysis for energy even in the presence of an adequate oxygen supply, a condition known as “aerobic glycolysis,” or the “Warburg effect.” Pyruvate dehydrogenase E1 subunit (PDHA1) is one of the main factors for the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and has been suggested to be closely associated with tumorigenesis. Here we observed that the PDHA1 protein was reduced in hepatocellular carcinoma (HCC) specimens by immunohistochemistry and Western blot, which was significantly associated with poor overall survival. To further analyze the function of PDHA1 in cancer cells, PDHA1 was upregulated in the HCC cell lines SMMC-7721 and HepG2. The results demonstrated that overexpression of the PDHA1 gene inhibited aerobic glycolysis with lower lactate via increased PDH activity; meanwhile, mitochondrial OXPHOS was enhanced accompanied with higher ATP and lower glucose consumption. We also found that apoptosis was promoted and intrinsic pathway proteins were increased in PDHA1-overexpressing cells. Collectively, our data indicate that reduced PDHA1 protein expression is associated with the poor clinical outcome of HCC. Upregulated PDHA1 gene expression can inhibit the Warburg effect and enhance the mitochondria-mediated apoptosis pathway.

---

Keywords

---