1. Academic Validation
  2. Necroptosis pathway blockage attenuates PFKFB3 inhibitor-induced cell viability loss and genome instability in colorectal cancer cells

Necroptosis pathway blockage attenuates PFKFB3 inhibitor-induced cell viability loss and genome instability in colorectal cancer cells

  • Am J Cancer Res. 2021 May 15;11(5):2062-2080.
Siyuan Yan 1 Qianqian Li 1 Deru Zhang 1 Xiaowen Wang 1 Yang Xu 1 Cong Zhang 1 Dongli Guo 2 Yonghua Bao 1
Affiliations

Affiliations

  • 1 Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University Jining 272067, China.
  • 2 Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University Jining 272000, China.
PMID: 34094669
Abstract

Cancer cells prone to utilize aerobic glycolysis other than oxidative phosphorylation to sustain its continuous cell activity in the stress microenvironment. Meanwhile, Cancer cells generally suffer from genome instability, and both radiotherapy and chemotherapy may arouse DNA strand break, a common phenotype of genome instability. Glycolytic Enzyme PFKFB3 (6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3), plays essential roles in variety physiology and pathology processes, and generally maintain high level in Cancer cells. Although this protein has been reported to involve in genome instability, its role remains unclear and controversial. Here, we showed that PFK-15, a PFKFB3 inhibitor, obviously induced Apoptosis, cell viability loss, and inhibited cell proliferation/migration. Besides, PFK-15 was also found to induce Necroptosis, as it not only up-regulated the phosphorylated RIP1, RIP3 and MLKL, but also enhanced the interaction between RIP3 and RIP1/MLKL, all of which are characterization of Necroptosis induction. Both genetically and pharmacologically deprivation of Necroptosis attenuated the cytotoxic effect of PFK-15. Besides, PFK-15 increased the γ-H2AX level and micronuclei formation, markers for genome instability, and inhibition of Necroptosis attenuated these phenotypes. Collectively, the presented data demonstrated that PFK-15 induced genome instability and Necroptosis, and deprivation of Necroptosis attenuated cytotoxicity and genotoxicity of PFK-15 in colorectal Cancer cells, thereby revealing a more intimate relationship among PFKFB3, Necroptosis and genome instability.

Keywords

PFKFB3; cell viability; colorectal cancer; genome instability; necroptosis.

Figures
Products
Inhibitors & Agonists
Other Products