Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer

Jiangjiang Li; Ya He; Zheqiong Tan; Jingchen Lu; Liling Li; Xin Song; Feng Shi; Longlong Xie; Shuo You; Xiangjian Luo; Namei Li; Yueshuo Li; Xiaolan Liu; Min Tang; Xinxian Weng; Wei Yi; Jia Fan; Jian Zhou; Gao Qiang; Shuang Jian Qiu; Weizhong Wu; Ann M. Bode; Ya Cao

doi:10.7150/thno.21524

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer

Jiangjiang Li, Ya He, Zheqiong Tan, Jingchen Lu, Liling Li, Xin Song, Feng Shi, Longlong Xie, Shuo You, Xiangjian Luo, Namei Li, Yueshuo Li, Xiaolan Liu, Min Tang, Xinxian Weng, Wei Yi, Jia Fan, Jian Zhou, Gao Qiang, Shuang Jian QiuWeizhong Wu, Ann M. Bode, Ya Cao

Hormel Institute

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

Original language	English (US)
Pages (from-to)	4050-4061
Number of pages	12
Journal	Theranostics
Volume	8
Issue number	15
DOIs	https://doi.org/10.7150/thno.21524
State	Published - 2018

Bibliographical note

Funding Information:
This work was supported by The National Basic Research Program of China (No. 2011CB504305) and the Natural Science Foundation of Hunan Province (No. 14JJ3039).

Publisher Copyright:
© Ivyspring International Publisher.

Keywords

HIF1-α
Isocitrate dehydrogenase 2
Lung cancer
Tumor growth
Warburg effect

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.7150/thno.21524

OpenUrl availability

Full text

Cite this

@article{cc112e683a9440569e2e754c4ba63695,

title = "Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer",

abstract = "Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.",

keywords = "HIF1-α, Isocitrate dehydrogenase 2, Lung cancer, Tumor growth, Warburg effect",

author = "Jiangjiang Li and Ya He and Zheqiong Tan and Jingchen Lu and Liling Li and Xin Song and Feng Shi and Longlong Xie and Shuo You and Xiangjian Luo and Namei Li and Yueshuo Li and Xiaolan Liu and Min Tang and Xinxian Weng and Wei Yi and Jia Fan and Jian Zhou and Gao Qiang and Qiu, {Shuang Jian} and Weizhong Wu and Bode, {Ann M.} and Ya Cao",

note = "Funding Information: This work was supported by The National Basic Research Program of China (No. 2011CB504305) and the Natural Science Foundation of Hunan Province (No. 14JJ3039). Publisher Copyright: {\textcopyright} Ivyspring International Publisher.",

year = "2018",

doi = "10.7150/thno.21524",

language = "English (US)",

volume = "8",

pages = "4050--4061",

journal = "Theranostics",

issn = "1838-7640",

publisher = "Ivyspring International Publisher",

number = "15",

}

TY - JOUR

T1 - Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer

AU - Li, Jiangjiang

AU - He, Ya

AU - Tan, Zheqiong

AU - Lu, Jingchen

AU - Li, Liling

AU - Song, Xin

AU - Shi, Feng

AU - Xie, Longlong

AU - You, Shuo

AU - Luo, Xiangjian

AU - Li, Namei

AU - Li, Yueshuo

AU - Liu, Xiaolan

AU - Tang, Min

AU - Weng, Xinxian

AU - Yi, Wei

AU - Fan, Jia

AU - Zhou, Jian

AU - Qiang, Gao

AU - Qiu, Shuang Jian

AU - Wu, Weizhong

AU - Bode, Ann M.

AU - Cao, Ya

N1 - Funding Information: This work was supported by The National Basic Research Program of China (No. 2011CB504305) and the Natural Science Foundation of Hunan Province (No. 14JJ3039). Publisher Copyright: © Ivyspring International Publisher.

PY - 2018

Y1 - 2018

N2 - Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

AB - Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

KW - HIF1-α

KW - Isocitrate dehydrogenase 2

KW - Lung cancer

KW - Tumor growth

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=85050278481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050278481&partnerID=8YFLogxK

U2 - 10.7150/thno.21524

DO - 10.7150/thno.21524

M3 - Article

C2 - 30128035

AN - SCOPUS:85050278481

SN - 1838-7640

VL - 8

SP - 4050

EP - 4061

JO - Theranostics

JF - Theranostics

IS - 15

ER -

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this