Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca2+ overload-induced ferroptosis

Yinyun Ni; Jiaye Liu; Lingyan Zeng; Ying Yang; Lei Liu; Menglin Yao; Li Chai; Lu Zhang; Yi Li; Li Zhang; Weimin Li

doi:10.3389/fphar.2022.1109822

Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca²⁺ overload-induced ferroptosis

Front Pharmacol. 2023 Jan 11:13:1109822. doi: 10.3389/fphar.2022.1109822. eCollection 2022.

Authors

Yinyun Ni¹, Jiaye Liu², Lingyan Zeng¹, Ying Yang¹, Lei Liu¹, Menglin Yao¹, Li Chai³, Lu Zhang³, Yi Li³, Li Zhang¹, Weimin Li^{1

4}

Affiliations

¹ Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network (NHC Key Laboratory of Transplant Engineering and Immunology), West China Hospital, Sichuan University, Chengdu, Sichuan, China.
² Department of Thyroid and Parathyroid Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
³ Institute of Core facility, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁴ Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Abstract

Background: Manoalide (MA), a proven natural inhibitor of PLA2 has anticancer effects, but its potential application and mechanism as an anticancer drug to promote EGFR-TKI sensitivity in lung cancer cells have not been studied. Methods: KRAS-mutated lung cancer cells and organoids, acquired osimertinib-resistant lung cancer cell lines HCC827OR, were used as EGFR-TKI-resistant models. CCK-8, clone formation, apoptosis assays, and calcein-AM staining were performed to investigate the inhibitory effects of MA in lung cancer cells and organoids. The flow cytometry or confocal microscope was used to detect lipid droplets, ROS, lipid peroxidation, mitochondria Ca²⁺, and iron content. The oxygen consumption rate (OCR) and fatty acid oxidation (FAO) were used to estimate the effect of MA on mitochondrial function. Results: MA inhibits the proliferation of KRAS-mutated lung cancer cells and organoids. In addition, MA induces ER stress in a ROS-dependent mechanism. The ROS induced by MA is mainly in mitochondrial and causes lipid peroxidation, thereby inhibiting mitochondrial FAO metabolism and promoting the accumulation of lipid droplets. MA also suppresses the KRAS-ERK pathway through ROS and promotes the sensitivity of KRAS-mutated lung cancer cells and organoids to osimertinib. Furthermore, MA induces ferroptosis by suppressing the NRF2-SLC7A11 axis and mitochondrial Ca²⁺ overload induced-FTH1 pathways to promote the sensitivity of osimertinib-resistant lung cancer cells to osimertinib. Conclusions: MA is a candidate EGFR-TKI sensitizer in KRAS-mutated and osimertinib-resistant lung cancer cells.

Keywords: EGFR-TKI resistance; ROS; ferroptosis; lung cancer; manoalide (MA); mitochondrial Ca2+.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos. 82173251 and 81974363 to LZ; 81871890 and 91859203 to WL); CAMS Innovation Fund for Medical Science (No. 2019TX310002); National Guided Science and Technology Development Project of Sichuan Province (No. 2020ZYD009); Fundamental Research Funds for the Central Universities (SCU2022D025).