Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma

doi:10.19401/j.cnki.1007-3639.2025.08.004

Abstract

Abstract:

Background and purpose: The aberrant activation of pyruvate dehydrogenase kinase 1 (PDK1) drives tumor microenvironment remodeling and metastasis through mediating the Warburg effect. As a critical tumor-suppressive phosphatase, phosphatase and tensin homolog deleted on chromoseme ten (PTEN) activates PDK1 via loss of expression to induce aerobic glycolysis and accelerate tumor progression. The molecular interplay between PDK1 and PTEN in kidney renal clear cell carcinoma (KIRC) urgently requires systematic elucidation. This study aimed to clarify how PTEN regulates PDK1 to inhibit malignant phenotypes in KIRC. Methods: Bioinformatics analysis was conducted to compare PTEN and PDK1 expression levels as well as their prognostic correlations in the Cancer Genome Atlas (TCGA)-KIRC datasets. KIRC cell models was established by either silencing PDK1 or enhancing its expression, subsequently evaluating their malignancy characteristics through cell counting kit-8 (CCK-8) proliferation, colony formation, cell migration, and invasion assays. To validate the regulatory interactions, we used PDK1-overexpressing cells treated with a PTEN-specific inhibitor. Western blot was used to dectect the protein expression. Results: The TCGA-KIRC analysis found significantly higher mRNA levels of PTEN and PDK1 in tumor tissues compared to normal controls (P<0.05), yet this high expression was associated with improved overall survival (P<0.01). Besides, a strong positive correlation was observed between PTEN and PDK1 expressions (r=0.52, P<0.001). Functional assays demonstrated that PDK1 knockdown markedly promoted cell proliferation, migration, and invasion, whereas PDK1 overexpression exhibited opposing effects. Mechanistically, inhibiting PTEN worsened malignant behaviors (P<0.01), however, these effects were reversed by overexpressing PDK1. Conclusion: This study presents the first evidence of the dual tumor-suppressive function of the PTEN-PDK1 biological axis in renal cancer, which supports the development of precision treatment strategies based on novel targets.

Key words: Clear cell renal cell carcinoma, PDK1, PTEN, Molecular mechanisms, Prognosis

CLC Number:

R737.11

DUAN Shuangshuang, GULINAIZAIER Abudusaimaiti, ZHANG Lijun, SUN Miao, LIU Huibin. Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma[J]. China Oncology, 2025, 35(8): 761-768.

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References 18

[1]	PHAM D X, HSU T. Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma[J]. J Biomed Sci, 2025, 32(1): 17.
[2]	CHOI S H, CHEN Y W, PANIAN J, et al. Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma[J]. Oncologist, 2025, 30(3): oyae276.
[3]	RAGHUBAR A M, ROBERTS M J, WOOD S, et al. Cellular milieu in clear cell renal cell carcinoma[J]. Front Oncol, 2022, 12: 943583.
[4]	GAN L L, YANG Y, LIANG Z Z, et al. Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation[J]. Eur J Med Chem, 2024, 264: 116008.
[5]	ZHOU Y, GUO Y Z, RAN M X, et al. Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing[J]. Cancer Lett, 2023, 577: 216425.
[6]	JANE E P, PREMKUMAR D R, RAJASUNDARAM D, et al. Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases[J]. Mol Oncol, 2022, 16(1): 219-249.
[7]	TUFAIL M. PTEN-mediated resistance in cancer: from foundation to future therapies[J]. Toxicol Rep, 2025, 14: 101987.
[8]	CHATTERJEE N, PAZARENTZOS E, MAYEKAR M K, et al. Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers[J]. Cell Rep, 2019, 28(9): 2317-2330.e8. doi: S2211-1247(19)30967-2 pmid: 31461649
[9]	ZHANG Y L, CHEN H L, YUAN R J, et al. PDK1-stabilized LncRNA SPRY4-IT1 promotes breast cancer progression via activating NF-κB signaling pathway[J]. Mol Carcinog, 2023, 62(7): 1009-1024.
[10]	SUN W H, CHEN Y H, LEE H H, et al. PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer[J]. Cancer Metab, 2022, 10(1): 23.
[11]	YANG Q, WU F, ZHANG Y, et al. FOXM1 regulates glycolysis in nasopharyngeal carcinoma cells through PDK1[J]. J Cell Mol Med, 2022, 26(13): 3783-3796. doi: 10.1111/jcmm.17413 pmid: 35656815
[12]	JR K W G. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma[J]. Clin Cancer Res, 2007, 13(2 Pt 2): 680s-684s.
[13]	KIM J W, TCHERNYSHYOV I, SEMENZA G L, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia[J]. Cell Metab, 2006, 3(3): 177-185.
[14]	FUKUSHI A, KIM H D, CHANG Y C, et al. Revisited metabolic control and reprogramming cancers by means of the Warburg effect in tumor cells[J]. Int J Mol Sci, 2022, 23(17): 10037.
[15]	GOLIAS T, PAPANDREOU I, SUN R, et al. Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours[J]. Sci Rep, 2016, 6: 31146. doi: 10.1038/srep31146 pmid: 27498883
[16]	MALIK M, MAQBOOL M, NISAR T, et al. Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach[J]. Oncol Res, 2023, 31(6): 899-916.
[17]	ALVES Â, MEDEIROS R, TEIXEIRA A L, et al. Decoding PTEN regulation in clear cell renal cell carcinoma: pathway for biomarker discovery and therapeutic insights[J]. Biochim Biophys Acta Rev Cancer, 2024, 1879(5): 189165.
[18]	LEE H J, LEE H Y, LEE J H, et al. Prognostic significance of biallelic loss of PTEN in clear cell renal cell carcinoma[J]. J Urol, 2014, 192(3): 940-946. doi: 10.1016/j.juro.2014.03.097 pmid: 24704020

Variable	TCGA (n=526)
Status n(%)
Alive	351 (66.7)
Death	175 (33.3)
Age
x±s	60.5±12.2
Median (Min, Max)	60.0 (26.0, 90.0)
Gender n(%)
Male	341 (64.8)
Female	185 (35.2)
Grade n(%)
1	13 (2.5)
2	229 (43.5)
3	207 (39.4)
4	77 (14.6)
Stage n(%)
Ⅰ	264 (50.2)
Ⅱ	54 (10.3)
Ⅲ	124 (23.6)
Ⅳ	84 (16.0)