TY - JOUR
T1 - Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth
AU - Liu, Yuan
AU - Murray-Stewart, Tracy
AU - Casero, Robert A.
AU - Kagiampakis, Ioannis
AU - Jin, Lihua
AU - Jiawen, Zhang
AU - Huihui, Wang
AU - Che, Qi
AU - Huan, Tong
AU - Ke, Jieqi
AU - Feizhou, Jiang
AU - Fangyuan, Wang
AU - Wan, Xiaoping
N1 - Funding Information:
This study was supported by grants from the National Natural Science Foundation of China (NSFC nos. 81172476, 811272885 and 81472427), Shanghai Science and Technology Committee Foundation Basic Research Field focused Project (13JC1404501), Doctoral Specialized Fund from Ministry of Education (20120073110090).
PY - 2017/6
Y1 - 2017/6
N2 - In order to improve the sensitivity of cervical cancer cells to irradiation therapy, we targeted hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis, and explore its role in cervical cancer cells. We suppressed HK2 expression and/ or function by shRNA and/or metformin and found HK2 inhibition enhanced cells apoptosis with accelerating expression of cleaved PARP and caspase-3. HK2 inhibition also induced much inferior proliferation of cervical cancer cells both in vitro and in vivo with diminishing expression of mTOR, MIB and MGMT. Moreover, HK2 inhibition altered the metabolic profile of cervical cancer cells to one less dependent on glycolysis with a reinforcement of mitochondrial function and an ablation of lactification ability. Importantly, cervical cancer cells contained HK2 inhibition displayed more sensitivity to irradiation. Further results indicated that HPV16 E7 oncoprotein altered the glucose homeostasis of cervical cancer cells into glycolysis by coordinately promoting HK2 expression and its downregulation of glycolysis. Taken together, our findings supported a mechanism whereby targeting HK2 inhibition contributed to suppress HPV16 E7-induced tumor glycolysis metabolism phenotype, inhibiting tumor growth, and induced apoptosis, blocking the cancer cell energy sources and ultimately enhanced the sensitivity of HPV(+) cervical cancer cells to irradiation therapy.
AB - In order to improve the sensitivity of cervical cancer cells to irradiation therapy, we targeted hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis, and explore its role in cervical cancer cells. We suppressed HK2 expression and/ or function by shRNA and/or metformin and found HK2 inhibition enhanced cells apoptosis with accelerating expression of cleaved PARP and caspase-3. HK2 inhibition also induced much inferior proliferation of cervical cancer cells both in vitro and in vivo with diminishing expression of mTOR, MIB and MGMT. Moreover, HK2 inhibition altered the metabolic profile of cervical cancer cells to one less dependent on glycolysis with a reinforcement of mitochondrial function and an ablation of lactification ability. Importantly, cervical cancer cells contained HK2 inhibition displayed more sensitivity to irradiation. Further results indicated that HPV16 E7 oncoprotein altered the glucose homeostasis of cervical cancer cells into glycolysis by coordinately promoting HK2 expression and its downregulation of glycolysis. Taken together, our findings supported a mechanism whereby targeting HK2 inhibition contributed to suppress HPV16 E7-induced tumor glycolysis metabolism phenotype, inhibiting tumor growth, and induced apoptosis, blocking the cancer cell energy sources and ultimately enhanced the sensitivity of HPV(+) cervical cancer cells to irradiation therapy.
KW - Cervical cancer
KW - Glycolysis
KW - HPV16 E7
KW - Hexokinase 2
KW - Irradiation
UR - http://www.scopus.com/inward/record.url?scp=85019587207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019587207&partnerID=8YFLogxK
U2 - 10.3892/ijo.2017.3979
DO - 10.3892/ijo.2017.3979
M3 - Article
C2 - 28498475
AN - SCOPUS:85019587207
SN - 1019-6439
VL - 50
SP - 2011
EP - 2023
JO - International journal of oncology
JF - International journal of oncology
IS - 6
ER -