PTEN loss promotes Warburg effect and prostate cancer cell growth by inducing FBP1 degradation

Abstract

RationaleFructose-1,6-bisphosphatase (FBP1) is a tumor suppressor and a key enzyme negatively regulating Warburg effect in cancer. However, regulation of FBP1 protein expression and its exact role in prostate cancer (PCa) is largely unclear. Phosphatase and tensin homolog (PTEN) is one of the most frequently deleted tumor suppressor genes in human PCa. However, the role of PTEN loss in aberrant Warburg effect in cancer remains poorly understood.MethodsExpression of PTEN and FBP1 was analyzed in several PCa cell lines and prostate tumor tissues in mice. Western blot (WB) and RT-PCR approaches were used to examine how PTEN regulates FBP1 expression. Co-immunoprecipitation (co-IP) and in vivo ubiquitination assays were used to define the regulatory mechanisms. A PCa xenograft model was employed to determine the impact of PTEN regulation of FBP1 on PCa growth in vivo.ResultWe demonstrated that in a manner dependent of PI3K/AKT signal pathway PTEN regulated FBP1 expression in various PCa cell lines and tumors in mice. We confirmed that this regulation took place at the protein level and was mediated by SKP2 E3 ubiquitin ligase. Mechanistically, we showed that serine 271 phosphorylation of FBP1 by cyclin-dependent kinases (CDKs) was essential for SKP2-mediated degradation of FBP1 protein induced by PTEN loss. Most importantly, we further showed that loss of PTEN expression enhanced Warburg effect and PCa growth in mice in a manner dependent, at least partially on FBP1 protein degradation.ConclusionsOur results reveal a novel tumor-suppressive feature of PTEN in restraining FBP1 degradation and the Warburg effect. These results also suggest that prohibiting FBP1 protein degradation could be a viable therapeutic strategy for PTEN-deficient PCa.

The Apoptotic and Anti-Warburg Effects of Brassinin in PC-3 Cells via Reactive Oxygen Species Production and the Inhibition of the c-Myc, SIRT1, and β-Catenin Signaling Axis

“…It is well documented that the Warburg effect enhances the consumption of glucose in several cancers compared to normal tissues under accelerated aerobic glycolysis [ 10 ]. Indeed, the Warburg effect is critically involved in prostate cancer progression [ 11 ], with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) loss [ 12 ] and glycolysis-associated proteins such as pyruvate kinase-M2 (PKM2), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDH) [ 13 , 14 ]. Hence, the inhibition of the Warburg effect is regarded as a therapeutic strategy in prostate cancer therapy [ 11 , 15 ].…”

“…with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) loss [12] and glycolysis-associated proteins such as pyruvate kinase-M2 (PKM2), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDH) [13,14]. Hence, the inhibition of the Warburg effect is regarded as a therapeutic strategy in prostate cancer therapy [11,15].…”

Icariin-Curcumol promotes docetaxel sensitivity in prostate cancer through modulation of the PI3K-Akt signaling pathway and the Warburg effect

“…The increased rate of glycolysis is considered a common metabolic change in cancer [ 44 ]. Enzymes involved in glucose metabolism have been found to be dysregulated in PCa, and the reduction in the Warburg effect has been shown to accompany inhibition of PCa xenograft tumor growth and drug resistance [ 45 , 46 ]. Inhibition of glycolysis has been suggested as a potential strategy to overcome cancer drug resistance [ 47 ].…”

FBP1 inhibits NSCLC stemness by promoting ubiquitination of Notch1 intracellular domain and accelerating degradation

“…FBP1 acts as a tumor suppressor in various cancer types. Specifically, FBP1 inhibits the potential Warburg effect by counteracting glycolytic flux in clear cell renal cell carcinoma [ 7 ], breast cancer [ 8 – 10 ], lung adenocarcinoma [ 11 , 12 ], hepatocellular carcinoma [ 13 , 14 ], and prostate cancer [ 15 ]. In basal-like breast cancer, the Snail-G9a-DNMT1 complex induces methylation of the FBP1 promoter, leading to down-regulation of FBP1.…”