Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to s...Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to stabilize the mitochondrial outer membrane,which inhibits cancer cell apoptosis.Therefore,HK2 has become a potential target for cancer treatment.Proteolysis targeting chimeras(PROTACs)are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation.Many potent and specific PROTACs targeting dissimilar targets have been developed.In this study,an HK2 PROTAC,4H-5P-M,was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome system.It was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose-and time-dependent manner and suppressed the growth of SW480 cells.4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase isozymes.Moreover,it could suppress glycolysis and accelerate the apoptosis of cancer cells.Therefore,it provided a new insight into the development of anti-tumor drugs.展开更多
基金Chunhui Program-Cooperative Research Project of the Ministry of EducationLiaoning Province Natural Science Foundation (No.2022-MS-241)+3 种基金Shenyang Young and Middle-aged Innovative Talents Support Program (No.RC210446)for financial supportsthe support from National-Local Joint Engineering Research Center for Molecular Biotechnology of Fujian&Taiwan TCMFujian Key Laboratory of Chinese Materia MedicaFujian University Key Laboratory for Research and Development of TCM Resources,at Fujian University of Traditional Chinese Medicine
文摘Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to stabilize the mitochondrial outer membrane,which inhibits cancer cell apoptosis.Therefore,HK2 has become a potential target for cancer treatment.Proteolysis targeting chimeras(PROTACs)are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation.Many potent and specific PROTACs targeting dissimilar targets have been developed.In this study,an HK2 PROTAC,4H-5P-M,was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome system.It was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose-and time-dependent manner and suppressed the growth of SW480 cells.4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase isozymes.Moreover,it could suppress glycolysis and accelerate the apoptosis of cancer cells.Therefore,it provided a new insight into the development of anti-tumor drugs.
