Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis

Jiang, Xiuxing; Huang, Xiangtao; Zheng, Guoxun; Jia, Guanfei; Li, Zhiqiang; Ding, Xin; Lei, Ling; Yuan, Liang; Xu, Shuangnian; Gao, Ning

doi:10.7150/thno.76563

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Theranostics 2022; 12(16):6972-6988. doi:10.7150/thno.76563 This issue Cite

Research Paper

Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis

Xiuxing Jiang^1*, Xiangtao Huang^2*, Guoxun Zheng^3*, Guanfei Jia¹, Zhiqiang Li¹, Xin Ding¹, Ling Lei¹, Liang Yuan⁴, Shuangnian Xu^2✉, Ning Gao^1,4✉

1. College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
2. Department of Hematology, Southwest Hospital, Army Medical University, Chongqing 400038, China.
3. Shanghai StoneWise AI Technology Co. Ltd. Shanghai 201210, China.
4. Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, China.
*These authors contributed equally to this work.

Citation:

Jiang X, Huang X, Zheng G, Jia G, Li Z, Ding X, Lei L, Yuan L, Xu S, Gao N. Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis. Theranostics 2022; 12(16):6972-6988. doi:10.7150/thno.76563. https://www.thno.org/v12p6972.htm

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Abstract

Background: The emergence of chemoresistance in leukemia markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Recent evidence has revealed that phosphatidylinositol 4 kinase-IIIα (PI4KA) plays a critical role in tumorigenesis. However, the molecular mechanisms of PI4KA-regulated chemoresistance and leukemogenesis remain largely unknown.

Methods: Liquid chromatography-mass spectrometry (LC-MS), patient samples and leukemia xenograft mouse models were used to investigate whether PI4KA was an effective target to overcome chemoresistance in leukemia. Enzyme-linked immunosorbent assay (ELISA) and molecular mechanics/generalized born surface area (MM/GBSA) method were employed to identify cepharanthine (CEP) as a novel PI4KA inhibitor.

Results: High expression of PI4KA was observed in drug-resistant leukemia cells or in relapsed leukemia patients, which was correlated with poor overall survival. Depletion of PI4KA sensitized drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo by regulating ERK/AMPK/OXPHOS axis. We also identified cepharanthine (CEP) as a novel PI4KA inhibitor, which could undermine the stability of the PI4KA/TTC7/FAM126 complex, enhancing the sensitivity of drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo.

Conclusions: Our study underscored the potential of therapeutic targeting of PI4KA to overcome chemoresistance in leukemia. A combination of the PI4KA inhibitor with classic chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of refractory leukemia.

Keywords: Leukemia, chemoresistance, PI4KA, ERK/AMPK/OXPHOS axis

Citation styles

APA

Jiang, X., Huang, X., Zheng, G., Jia, G., Li, Z., Ding, X., Lei, L., Yuan, L., Xu, S., Gao, N. (2022). Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis. Theranostics, 12(16), 6972-6988. https://doi.org/10.7150/thno.76563.

ACS

Jiang, X.; Huang, X.; Zheng, G.; Jia, G.; Li, Z.; Ding, X.; Lei, L.; Yuan, L.; Xu, S.; Gao, N. Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis. Theranostics 2022, 12 (16), 6972-6988. DOI: 10.7150/thno.76563.

NLM

CSE

Jiang X, Huang X, Zheng G, Jia G, Li Z, Ding X, Lei L, Yuan L, Xu S, Gao N. 2022. Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis. Theranostics. 12(16):6972-6988.

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