Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15

Sheng Fan Wang*, Yuh Lih Chang, Ting Yu Liu, Kuo Hung Huang, Wen Liang Fang, Anna Fen Yau Li, Tien Shun Yeh, Giun Yi Hung, Hsin Chen Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Gastric neoplasm is a high-mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy-treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4-C/EBP homologous protein pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species-activated general control nonderepressible 2 mediates the oligomycin-induced ISR, and upregulates GDF15. The GDF15–glial cell-derived neurotrophic factor family receptor a-like–ISR–cystine/glutamate transporter-enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15–ISR regulation might be a strategy against cisplatin resistance of gastric cancer.

Original languageEnglish
Pages (from-to)1131-1150
Number of pages20
JournalFEBS Journal
Volume291
Issue number6
DOIs
StatePublished - Mar 2024

Keywords

  • chemoresistance
  • gastric cancer
  • growth differentiation factor 15
  • integrated stress response
  • mitochondria

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