Mitochondrial phosphoenolpyruvate carboxykinase inhibits kidney renal clear cell carcinoma malignant progression, leading to cell energy metabolism imbalance

Yeda Chen; Zhu Wang; Qiong Deng; Yuting Chen; Hui Liang

Mitochondrial phosphoenolpyruvate carboxykinase inhibits kidney renal clear cell carcinoma malignant progression, leading to cell energy metabolism imbalance

Am J Cancer Res. 2023 Mar 15;13(3):886-899. eCollection 2023.

Authors

Yeda Chen¹, Zhu Wang¹, Qiong Deng¹, Yuting Chen², Hui Liang¹

Affiliations

¹ Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital) Shenzhen 518109, Guangdong, China.
² Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University Dongguan 518109, Guangdong, China.

PMID: 37034209
PMCID: PMC10077028

Abstract

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a key gluconeogenesis enzyme. Its differential expression is related to kidney renal clear cell carcinoma (KIRC) malignancy, possibly by influencing energy metabolism. Therefore, it is possible that PKC2 plays a significant part in the emergence and progression of KIRC. To systematically and comprehensively identify the significance of PCK2 in KIRC, we further studied PCK2 in terms of its relationship to clinical features and various clinical subgroups' prognoses. Moreover, we verified the effect of PCK2 and KIRC cells using experimental methods. PCR and western blotting analyses confirmed PCK2 expression in KIRC cell lines and tissues. As a cell model, we constructed cells that overexpress PCK2. Proliferation was detected by EdU experiments. Scratch tests and transwell assays were used, respectively, to analyze cell migration and invasion. Mass spectrometry detected energy metabolite expression in KIRC cells. The findings revealed that KIRC patients with lower levels of PCK2 expression exhibited shorter progression-free intervals, shorter disease-specific survival, and shorter overall survival. The experimental results showed that compared with 293t, PCK2 was downregulated in three KIRC lines (OSRC-2, 786-O, and A498). Relative to surrounding tissues, PCK2 was downregulated in KIRC. PCK2 overexpression inhibited KIRC cell proliferation, migration, and invasion and upregulated energy metabolite expression. Mass spectrometry revealed that thiamine pyrophosphate, cyclic AMP, beta-D-fructose 6-phosphate, lactate, flavin mononucleotide, NAD, NADP, and D-glucose 6-phosphate were upregulated. PCK2 has the potential to serve as both a diagnostic and prognostic molecular biomarker for KIRC, as well as an independent prognostic risk factor for KIRC. It is hoped that PCK2 will emerge as a therapeutic target for KIRC.

Keywords: Mitochondrial phosphoenolpyruvate carboxykinase; energy metabolism; invasion; kidney renal clear cell carcinoma; migration; proliferation.