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Mitochondrial dysfunction and cisplatin sensitivity in gastric cancer: GDF15 as a master player
1Institute for Biochemical Aging Research, University of Innsbruck, Austria.
Abstract:
Gastric cancer, a major global health concern, poses challenges in effective treatment, notably due to chemoresistance. This study investigates the role of growth/differentiation factor-15 (GDF-15) in mitochondrial dysfunction and its impact on cisplatin sensitivity in gastric cancer cells. In this issue of The FEBS Journal, Wang et al. demonstrate that GDF15 upregulation is associated with cisplatin insensitivity, mediated by the ATF4-CHOP pathway and reactive oxygen species-activated general control nonderepressible 2 [Wang S-F et al. (2023) FEBS J, https://doi.org/10.1111/febs.16992]. Connecting these insights, we explore the broader implications of GDF15 expression in the aging-cancer axis, particularly its involvement in cellular senescence and the senescence-associated secretory phenotype (SASP). This study suggests that GDF15 released by senescent cells could contribute to tumor progression, indicating potential avenues for therapeutic intervention by targeting senescent cells and their SASP. While the study provides valuable insights into mitigating cisplatin resistance, further research is crucial to fully understand the role of GDF15 in the tumor microenvironment and its potential feedback loops promoting tumorigenesis.
Insights
Growth/differentiation factor-15 (GDF-15) upregulation promotes cisplatin resistance in gastric cancer by inducing mitochondrial dysfunction. Targeting GDF-15 or senescent cells may offer new therapeutic strategies for chemoresistant gastric tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Gastric cancer presents significant treatment challenges, particularly chemoresistance.
- Mitochondrial dysfunction is implicated in cancer progression and treatment failure.
- Growth/differentiation factor-15 (GDF-15) is a cytokine with roles in stress response and cancer.
Purpose of the Study:
- To investigate the role of GDF-15 in cisplatin resistance in gastric cancer.
- To elucidate the molecular mechanisms linking GDF-15, mitochondrial dysfunction, and chemoresistance.
- To explore the connection between GDF-15, cellular senescence, and the tumor microenvironment.
Main Methods:
- Analysis of GDF-15 expression in gastric cancer cells.
- Investigation of the ATF4-CHOP pathway and reactive oxygen species (ROS) in GDF-15-mediated resistance.
- Assessment of GDF-15's impact on mitochondrial function and cisplatin sensitivity.
- Exploration of GDF-15's role in cellular senescence and the senescence-associated secretory phenotype (SASP).
Main Results:
- GDF-15 upregulation correlates with decreased sensitivity to cisplatin in gastric cancer cells.
- GDF-15 mediates cisplatin resistance through the ATF4-CHOP pathway and ROS generation.
- GDF-15 contributes to mitochondrial dysfunction, exacerbating chemoresistance.
- GDF-15 released by senescent cells may promote tumor progression via SASP.
Conclusions:
- GDF-15 is a key mediator of cisplatin resistance in gastric cancer, involving mitochondrial dysfunction and the ATF4-CHOP pathway.
- GDF-15's role in cellular senescence and SASP suggests a link to tumor progression.
- Targeting GDF-15 or senescent cells represents a potential therapeutic strategy for overcoming chemoresistance in gastric cancer.
