Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer

Yinan Xiao,Ye Guan,Ling Jin,Sayantani Sarkar Bhattacharya,Eleftheria Kalogera,Chaolin Deng,Viji Shridhar,Haotian Xu,Prabhu Thirusangu,Upasana Ray,Julie Staub,Xiaoling Fang

doi:10.1038/s41388-020-01621-4

Abstract

The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients.

Highlights

IntroductionMost endometrial cancer (EC) is effectively treated with surgery, chemotherapy with platinumbased drug(s), the response rates for advanced or recurrent disease are low [1, 4, 5]
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries [1], with an estimated 65,620 new cases and 12,590 deaths from endometrial cancer (EC) in 2020 [2]
Among the EC cells tested, significant expression of p-PFKFB3 was observed in EN1, HEC-1A, HEC-1B, ARK-2 and SPAC1L cell lines

Summary

Introduction

Most EC is effectively treated with surgery, chemotherapy with platinumbased drug(s), the response rates for advanced or recurrent disease are low [1, 4, 5]. The upregulation of glycolysis is one of the major metabolic pathways implicated in cancer progression. PFKFB3 plays an important role in regulating several cellular events, including pathological angiogenesis [15], carcinogenesis [6], cell cycle regulation [16], DNA repair [17], vessel sprouting [18], metastasis [19], and response to chemotherapy [14, 19]. Based on the regulatory function of PFKFB3 in glycolysis and cellular metabolism, an increasing number of studies have focused on investigating its role in tumor growth [8, 9]. Little is known about the role of PFKFB3 in EC and, further studies are needed

Methods

Results

Conclusion