Affiliation:
1. Nanfang Hospital, Southern Medical University
Abstract
Abstract
6-phosphofructo-2-kinase (PFKFB3) is an isoenzyme of the PFKFB family, of which numerous studies have revealed the involvement in tumorigenesis and malignant behaviors in a non-glycolysis-dependent manner. Based on our findings of PFKFB3 in trastuzumab resistance, interestingly, we have found that PFKFB3 significantly attenuated cisplatin cytotoxicity both in vivo and in vitro. We demonstrated that overexpression of PFKFB3 markedly inhibited Erastin- and cisplatin-induced ferroptotic cell death. We further showed that Cystine/glutamate antiporter (xCT) interacts with the phosphatase domain of PFKFB3 and can be dephosphorylated at serine 26 (S26) by PFKFB3. The dephosphorylation of S26 greatly enhances xCT transporter activity, is critical for the production of GSH, and inhibits cisplatin-induced ferroptosis. Notably, erastin reversed PFKFB3-mediated resistance to cisplatinboth in vivo and in vitro. Collectively, our findings open a door to uncover how PFKFB3 promotes cisplatin resistance and may provide a potential target for gastric cancer treatment.
Publisher
Research Square Platform LLC
Reference30 articles.
1. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries;Sung H;CA: a cancer journal for clinicians,2021
2. Gastric cancer;Smyth EC;Lancet (London, England),2020
3. The first metal based anticancer drug;Ghosh S;Bioorganic chemistry,2019
4. Molecular mechanisms of cisplatin resistance;Galluzzi L;Oncogene,2012
5. Cisplatin in cancer therapy: molecular mechanisms of action;Dasari S;European journal of pharmacology,2014