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    • The glycolytic activator phosphofructo kinase fructose bisph

    2021-12-03

    The glycolytic activator 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3 (PFKFB3) is well-known as a downstream substrate of hypoxia-inducible factor 1α (HIF-1α) signaling pathway [5,6]. Tumor hypoxia has long been associated with increased malignancy, poor prognosis and drug resistance. HIF-1α is a key regulator of hypoxia-dependent transcriptional responses and glycolysis. Increased expression of HIF-1α protein has been observed in a wide range of human cancer cell types, and associated with poor prognosis in many cases [7,8]. Overexpression of PFKFB3 enhances glycolysis and increases vessel formation [9]. Silencing of PFKFB3 in tumor ARM1 reduces tumor cell growth, invasion, intravasation and metastasis and improves chemotherapy of primary and metastatic tumors [10]. Nevertheless, the role of PFKFB3/HIF-1α axis in sorafenib resistance in HCC has not been fully understood. Therefore, in order to solve the predicament of current sorafenib therapy it is necessary to deepen the understanding of the underlying molecular mechanism.
    Materials and methods
    Results
    Discussion Next, to investigate the potential role of PFKFB3 in HCC sorafenib resistance, we first identified sorafenib IC50 of HCC cell lines and then generated PFKFB3 knockdown in the relative sorafenib-tolerant cells, CCK-8 and flow cytometry assays suggested that knockdown of PFKFB3 aggravated sorafenib-induced HCC cell viability inhibition and cell apoptosis induction. Moreover, our immunoblotting assay showed that PFKFB3 was significantly elevated after sorafenib treatment and PFKFB3 deficiency increased the expression of pro-apoptotic molecule. These findings revealed a potential role of PFKFB3 in mediating the efficacy of sorafenib treatment. According to previous studies, PFKFB3 is implicated in the regulation of tumor progression. PFKFB3 expression has been found to be significantly increased in a variety of solid tumors, including astrocytomas [20], breast cancer [21], colon carcinoma [22], renal cancer [23], lung adenocarcinoma [24], head and neck squamous cell carcinoma [25], ovarian cancer [26], prostatic carcinoma [23], pancreatic and gastric cancer [27] and thyroid cancer [23]. Some research suggested that PFKFB3 mediates glycolysis and survival in breast cancer cells [28]. On the other hand, PFKFB3 promotes vessel formation and reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis, which improves the delivery and efficacy of chemotherapy [29,30]. It was reported that tumor hypoxia and HIF-1α play crucial roles in disease progression and treatment resistance [31]. HIF-1α is expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and its expression is associated with different disease states [32]. While other studies demonstrated that HIF-1α is a key transcription factor driving PFKFB3 expression in macrophages [33]. Herein, our results confirm for the first time that a reciprocal regulatory interaction exists between PFKFB3 and HIF-1α. Specifically, PFKFB3 promoted sorafenib resistance to HCC via the PFKFB3/HIF-1α positive feedback loop, highlighting a novel mechanism utilized by cancer cells to generate therapy resistance. Overall, our study demonstrated that targeting the PFKFB3/HIF-1α axis may offer a novel therapeutic approach to block sorafenib resistance of HCC patients.
    Conflicts of interest
    Acknowledgements This work was supported by National Nature Science Foundation of China (Grant Nos. 81773008 and 81672756), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015), the Natural Science Foundation of Guangdong Province (Grant No. 2017A030311023), and the Science and Technology Plan of Guangzhou City (Grant No. 201804010044).
    Introduction Hypoxia induced factor 1 (HIF-1) is a transcription factor greatly affecting the survival of tumor cells under hypoxia microenvironment (Brown, 1999), which could bring about radiotherapy treatment failure and anticancer drugs resistance (Nagle and Zhou, 2006). HIF-1 inhibition has thus been recognized as an effective way in cancer therapy, raising numerous efforts that identify HIF-1 inhibitors from natural resource. Various natural products have been discovered to exhibit profound HIF-1 inhibitory effects (Nagle and Zhou, 2012; Du et al., 2013).