Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth

Yuan Liu, Tracy Murray Stewart, Robert A Casero, Ioannis Kagiampakis, Lihua Jin, Zhang Jiawen, Wang Huihui, Qi Che, Tong Huan, Jieqi Ke, Jiang Feizhou, Wang Fangyuan, Xiaoping Wan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2011-2023
Number of pages13
JournalInternational Journal of Oncology
Volume50
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Hexokinase
Uterine Cervical Neoplasms
Glycolysis
Growth
Neoplasms
Apoptosis
Metabolome
Metformin
Oncogene Proteins
Caspase 3
Small Interfering RNA
Homeostasis
Down-Regulation
Phenotype
Glucose

Keywords

  • Cervical cancer
  • Glycolysis
  • Hexokinase 2
  • HPV16 E7
  • Irradiation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth. / Liu, Yuan; Murray Stewart, Tracy; Casero, Robert A; Kagiampakis, Ioannis; Jin, Lihua; Jiawen, Zhang; Huihui, Wang; Che, Qi; Huan, Tong; Ke, Jieqi; Feizhou, Jiang; Fangyuan, Wang; Wan, Xiaoping.

In: International Journal of Oncology, Vol. 50, No. 6, 01.06.2017, p. 2011-2023.

Research output: Contribution to journalArticle

Liu, Y, Murray Stewart, T, Casero, RA, Kagiampakis, I, Jin, L, Jiawen, Z, Huihui, W, Che, Q, Huan, T, Ke, J, Feizhou, J, Fangyuan, W & Wan, X 2017, 'Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth', International Journal of Oncology, vol. 50, no. 6, pp. 2011-2023. https://doi.org/10.3892/ijo.2017.3979
Liu, Yuan ; Murray Stewart, Tracy ; Casero, Robert A ; Kagiampakis, Ioannis ; Jin, Lihua ; Jiawen, Zhang ; Huihui, Wang ; Che, Qi ; Huan, Tong ; Ke, Jieqi ; Feizhou, Jiang ; Fangyuan, Wang ; Wan, Xiaoping. / Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth. In: International Journal of Oncology. 2017 ; Vol. 50, No. 6. pp. 2011-2023.
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