PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

Wen-Kai Shi,Xiao-Dong Zhu,Hao Cai,Yuan-Yuan Zhang,Kang-Shuai Li,Xiao-Long Li,Man-Qing Cao,Cheng-Hao Wang,Hui-Chuan Sun,Shi-Zhe Zhang

doi:10.1038/s41419-018-0435-y

Abstract

Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key molecule of glucose metabolism in cytoplasm, has been found in various tumors. Emerging evidence has suggested that PFKFB3 is also located in the nucleus and apparent in regulatory functions other than glycolysis. In this study, we found that PFKFB3 expression is associated with hepatocellular carcinoma (HCC) growth and located mainly in the nucleus of tumor cells. PFKFB3 overexpression was associated with large tumor size (p = 0.04) and poor survival of patients with HCC (p = 0.027). Knockdown of PFKFB3 inhibited HCC growth, not only by reducing glucose consumption but also by damaging the DNA repair function, leading to G2/M phase arrest and apoptosis. In animal studies, overexpression of PFKFB3 is associated with increased tumor growth. Mechanistically, PFKFB3 silencing decreased AKT phosphorylation and reduced the expression of ERCC1, which is an important DNA repair protein. Moreover, PFK15, a selective PFKFB3 inhibitor, significantly inhibited tumor growth in a xenograft model of human HCC. PFKFB3 is a potential novel target in the treatment of HCC.

Highlights

Primary liver cancer is the second most common cause of cancer-related death in the world, and 90% of liver cancers are hepatocellular carcinoma (HCC)[1]
Expression of PFKFB3 in HCC cells and correlated with the survival of HCC patients To explore the clinical significance of PFKFB3 in HCC, we first performed a Kaplan–Meier survival analysis based on the data of The Cancer Genome Atlas (TCGA), which included 374 HCC patients divided into two groups with high or low expressions of PFKFB3 according to the median value of PFKFB3 expression
PFKFB3 expression was higher in seven HCC cell lines compared with that in L02 assayed by Western blot

Summary

Introduction

Primary liver cancer is the second most common cause of cancer-related death in the world, and 90% of liver cancers are hepatocellular carcinoma (HCC)[1]. Curative treatment provides long-term survival for patients during early stage HCC (Barcelona clinic liver cancer (BCLC) stage 0 and A), approximately 70% of patients have the advanced stage; they are not amenable for curative treatment, and the survival of these patients is poor[2]. Survival associated with systemic treatment, such as sorafenib, for advanced stage cancer patients is approximately 3 months[3]. One of the altered genes is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which significantly accelerates the glycolysis rate and is expressed in rapidly multiplying cells and various human cancers[6,7]. In breast and ovarian cancer cell line models, the PFKFB3 inhibitor 3-PO suppresses glycolytic flux and tumor growth[9]. In a study of head and neck squamous cell carcinoma, blocking PFKFB3 suppressed tumor growth and metastasis mediated by suppressing glycolysis[10]

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Conclusion