TY - JOUR
T1 - IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer
AU - Shigeta, Keisuke
AU - Hasegawa, Masanori
AU - Hishiki, Takako
AU - Naito, Yoshiko
AU - Baba, Yuto
AU - Mikami, Shuji
AU - Matsumoto, Kazuhiro
AU - Mizuno, Ryuichi
AU - Miyajima, Akira
AU - Kikuchi, Eiji
AU - Saya, Hideyuki
AU - Kosaka, Takeo
AU - Oya, Mototsugu
N1 - Funding Information:
The authors thank Noriyo Hayakawa and Tomomi Matsuura for technical assistance with metabolome analysis (Department of Clinical and Translational Research center, Keio University School of Medicine). This work was supported in part by a Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant numbers 21K20811 and 22K16809 to K.S. and grant number 20H03817 and 21K19579 to T.K.), by the Keio Medical Association Grant (to K.S.), by the 2019 Japanese Foundation for Research and Promotion of Endoscopy (JFE) Grant (to K.S.), by 2020 Keio University Graduate School Doctoral Program Grant (to K.S.), and by 2020 Keio Medical Otsuka Fumon/Fusako Fellowship Grant (to K.S.).
Funding Information:
The authors thank Noriyo Hayakawa and Tomomi Matsuura for technical assistance with metabolome analysis (Department of Clinical and Translational Research center, Keio University School of Medicine). This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant numbers 21K20811 and 22K16809 to K.S. and grant number 20H03817 and 21K19579 to T.K.), by the Keio Medical Association Grant (to K.S.), by the 2019 Japanese Foundation for Research and Promotion of Endoscopy (JFE) Grant (to K.S.), by 2020 Keio University Graduate School Doctoral Program Grant (to K.S.), and by 2020 Keio Medical Otsuka Fumon/Fusako Fellowship Grant (to K.S.).
Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2023/2/15
Y1 - 2023/2/15
N2 - Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.
AB - Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.
KW - chemoresistance
KW - hypoxia-inducible factor-1α
KW - isocitrate dehydrogenase 2
KW - metabolomic reprogramming
KW - urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85146357190&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85146357190&partnerID=8YFLogxK
U2 - 10.15252/embj.2022110620
DO - 10.15252/embj.2022110620
M3 - Article
C2 - 36637036
AN - SCOPUS:85146357190
SN - 0261-4189
VL - 42
JO - EMBO Journal
JF - EMBO Journal
IS - 4
M1 - e110620
ER -
