FBP1 regulates proliferation, metastasis, and chemoresistance by participating in C-MYC/STAT3 signaling axis in ovarian cancer

Haoran Li,Mingming Liu,Mengjiao Li,Yangyang Pang,Midie Xu,Yufei Yang,Zihao Qi,Ziliang Wang,Xi Cheng,Yongdong Niu

doi:10.1038/s41388-021-01957-5

Abstract

Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.

Highlights

Epithelial ovarian carcinoma is the most malignant tumor of the female reproductive system
We studied whether there was a correlation between FBP1 protein levels, metastasis, and SUV values using preoperative PET/CT scan data and immunohistochemical staining data from 100 ovarian carcinoma patients
We found that patients with no metastasis had high-FBP1 protein levels, whereas patients with metastasis presented with low-FBP1 levels; in addition, SUVmax values were significantly lower in patients with high-FBP1 protein levels than in those with low-FBP1 protein staining (Fig. 1E, F)

Summary

Introduction

Epithelial ovarian carcinoma is the most malignant tumor of the female reproductive system. Despite recent advances in epithelial ovarian carcinoma detection and treatment, the overall prognosis remains poor [1]. Tumor cells have a higher rate of aerobic glycolysis than oxidative phosphorylation [3,4,5]. FBP1, the rate-limiting enzyme in glycolysis, catalyzes the hydrolysis of fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate and inorganic phosphate. F-1,6-BP is a known allosteric activator of Pyruvate kinase isozyme type M2 (PKM2), which is an important enzyme in glycolysis. FBP1 may inhibit the effect of glycolysis in tumor cells [6, 7]. Low expression of FBP1 is regarded as a potential prognostic factor for malignancies including gastric cancer, breast cancer, and lung cancer [8, 9]

Objectives

Methods

Results

Conclusion