PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA

Liang Shi; Shuxian An; Ying Liu; Jianjun Liu; Feng Wang

doi:10.2147/OTT.S241717

PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA

Onco Targets Ther. 2020 Mar 30:13:2613-2627. doi: 10.2147/OTT.S241717. eCollection 2020.

Authors

Liang Shi^#^{1

2}, Shuxian An^#², Ying Liu³, Jianjun Liu², Feng Wang¹

Affiliations

¹ Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, Jiangsu, People's Republic of China.
² Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
³ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, Shanghai 200072, People's Republic of China.

^# Contributed equally.

Abstract

Background: Suppressed gluconeogenesis and increased glycolysis are common in clear cell renal cell carcinoma (ccRCC). Phosphoenolpyruvate carboxykinase 1 (PCK1) is a rate-limiting gluconeogenesis enzyme. However, the role of PCK1 in tumor metabolism and progression remains unclear.

Methods: Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo. Sixty-two patients with ccRCC underwent ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography. The levels of PCK1 and lactate dehydrogenase A (LDHA) in ccRCC tissues and peritumor tissues were investigated with immunohistochemistry. The relationships between ¹⁸F-FDG accumulation and the expression of PCK1 and LDHA were analyzed. The mechanisms underlying the regulation of LDHA by PCK1 were analyzed using in vitro molecular techniques.

Results: PCK1 suppressed ccRCC cell growth and metastasis in vitro and inhibited tumorigenesis in nude mice by blocking the aerobic glycolysis pathway. Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC. The expression level of PCK1 was negatively correlated with tumor progression, the LDHA expression level and ¹⁸F-FDG accumulation in primary ccRCC tissue. We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation. Finally, we showed that the effects of PCK1 on glucose metabolism, cell proliferation and metastasis are mediated via the inhibition of LDHA.

Conclusion: Our study identified a novel molecular mechanism underlying the Warburg effect. PCK1 may serve as a candidate prognostic biomarker, and targeting the PCK1/LDHA pathway might be a new strategy to selectively inhibit tumor metabolism in human ccRCC.

Keywords: LDHA; PCK1; clear cell renal cell carcinoma; glycolysis.