Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol

Yi Jie Ren, Xiao Hui Wang, Cheng Ji, Yi Di Guan, Xian Jiu Lu, Xian Rong Liu, Hong Han Zhang, Ling Chuan Guo, Qiong Hua Xu, Wei Dong Zhu, Zhi Jun Ming, Jin-Ming Yang, Yan Cheng, Yi Zhang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.

Original languageEnglish (US)
Article number804
JournalFrontiers in Pharmacology
Volume8
Issue numberNOV
DOIs
StatePublished - Nov 7 2017

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Nucleus Accumbens
Oxidative Stress
Neoplasms
Glycolysis
Oxygen Consumption
Reactive Oxygen Species
Respiration
Therapeutics
Cell Hypoxia
Physiological Stress
Nuclear Proteins
Pyruvic Acid
Heterografts
Hypoxia
elesclomol
Oxidoreductases
Apoptosis
Oxygen
Genes
pyruvate dehydrogenase (acetyl-transferring) kinase

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Ren, Yi Jie ; Wang, Xiao Hui ; Ji, Cheng ; Guan, Yi Di ; Lu, Xian Jiu ; Liu, Xian Rong ; Zhang, Hong Han ; Guo, Ling Chuan ; Xu, Qiong Hua ; Zhu, Wei Dong ; Ming, Zhi Jun ; Yang, Jin-Ming ; Cheng, Yan ; Zhang, Yi. / Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol. In: Frontiers in Pharmacology. 2017 ; Vol. 8, No. NOV.
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abstract = "In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.",
author = "Ren, {Yi Jie} and Wang, {Xiao Hui} and Cheng Ji and Guan, {Yi Di} and Lu, {Xian Jiu} and Liu, {Xian Rong} and Zhang, {Hong Han} and Guo, {Ling Chuan} and Xu, {Qiong Hua} and Zhu, {Wei Dong} and Ming, {Zhi Jun} and Jin-Ming Yang and Yan Cheng and Yi Zhang",
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Ren, YJ, Wang, XH, Ji, C, Guan, YD, Lu, XJ, Liu, XR, Zhang, HH, Guo, LC, Xu, QH, Zhu, WD, Ming, ZJ, Yang, J-M, Cheng, Y & Zhang, Y 2017, 'Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol', Frontiers in Pharmacology, vol. 8, no. NOV, 804. https://doi.org/10.3389/fphar.2017.00804

Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol. / Ren, Yi Jie; Wang, Xiao Hui; Ji, Cheng; Guan, Yi Di; Lu, Xian Jiu; Liu, Xian Rong; Zhang, Hong Han; Guo, Ling Chuan; Xu, Qiong Hua; Zhu, Wei Dong; Ming, Zhi Jun; Yang, Jin-Ming; Cheng, Yan; Zhang, Yi.

In: Frontiers in Pharmacology, Vol. 8, No. NOV, 804, 07.11.2017.

Research output: Contribution to journalArticle

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T1 - Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol

AU - Ren, Yi Jie

AU - Wang, Xiao Hui

AU - Ji, Cheng

AU - Guan, Yi Di

AU - Lu, Xian Jiu

AU - Liu, Xian Rong

AU - Zhang, Hong Han

AU - Guo, Ling Chuan

AU - Xu, Qiong Hua

AU - Zhu, Wei Dong

AU - Ming, Zhi Jun

AU - Yang, Jin-Ming

AU - Cheng, Yan

AU - Zhang, Yi

PY - 2017/11/7

Y1 - 2017/11/7

N2 - In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.

AB - In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.

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U2 - 10.3389/fphar.2017.00804

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