2. Academic Validation
  3. Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation

  • Signal Transduct Target Ther. 2022 Sep 12;7(1):317. doi: 10.1038/s41392-022-01131-7.
Guan-Nan Li  # 1 2,  Xue-Jiao Zhao  # 1 2,  Zhen Wang  # 1 2,  Meng-Shi Luo 1 2,  Shen-Nan Shi 1 2,  Dan-Mei Yan 1 2,  Hua-Yi Li 1 2,  Jia-Hao Liu 1 2,  Yang Yang 1 3,  Jia-Hong Tan 1 2,  Ze-Yu Zhang 1 2,  Ru-Qi Chen 1 2,  Hui-Ling Lai 4,  Xiao-Yuan Huang 1 2,  Jian-Feng Zhou 1 3,  Ding Ma 1 2,  Yong Fang 5 6,  Qing-Lei Gao 7 8
Affiliations

Affiliations

  • 1 Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
  • 3 Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
  • 4 Department of Gynecology, the Sixth Affiliated Hospital, Sun Yat-Sen University, 510000, Guangzhou, Guangdong, China.
  • 5 Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China. tongjify@163.com.
  • 6 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China. tongjify@163.com.
  • 7 Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China. qingleigao@hotmail.com.
  • 8 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China. qingleigao@hotmail.com.
  • # Contributed equally.
PMID: 36097006 DOI: 10.1038/s41392-022-01131-7
Abstract

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for Cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an Autophagy Inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent Paraptosis by hyperactivating the MAPK pathway in multiple Cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced Paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced Paraptosis and Autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering Paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian Cancer.

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