Mitochondrial ClpX Inhibition Induces Ferroptosis and Blocks Pancreatic Cancer Cell Proliferation

Area of Science:

• Molecular Biology
• Cancer Research
• Mitochondrial Biology

Background:

• Mitochondrial protein homeostasis is crucial, with caseinolytic protease P (ClpP) targeting being an established anticancer strategy.
• The role of caseinolytic protease X (ClpX), the ATPase partner in the ClpXP complex, in cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is largely unknown.
• Elevated CLPX expression in PDAC correlates with poor patient prognosis, suggesting an oncogenic role.

Purpose of the Study:

• To investigate the function of ClpX in pancreatic ductal adenocarcinoma (PDAC) pathogenesis.
• To explore the potential of ClpX as a therapeutic target for PDAC.

Main Methods:

• Investigated the effect of CLPX knockdown on PDAC cell mitochondrial homeostasis and proliferation.
• Analyzed mitochondrial dysfunction markers including oxidative stress, unfolded protein response (UPR), and ferroptosis.
• Screened ATPase inhibitors to identify compounds targeting ClpX activity.

Main Results:

• CLPX knockdown impaired PDAC cell proliferation by disrupting mitochondrial homeostasis and reducing oxidative phosphorylation.
• ClpX inhibition induced mitochondrial dysfunction, leading to increased oxidative stress, UPR, and ferroptosis, evidenced by elevated reactive oxygen species, ferrous iron, lipid peroxidation, and malondialdehyde.
• The ATPase inhibitor MSC1094308 effectively suppressed ClpXP activity, inducing UPR and ferroptosis in PDAC cells.

Conclusions:

• ClpX plays a significant oncogenic role in pancreatic ductal adenocarcinoma by maintaining mitochondrial homeostasis.
• ClpX inhibition triggers multiple cell death pathways, including UPR and ferroptosis, in PDAC cells.
• Targeting ClpX represents a promising novel therapeutic strategy for pancreatic ductal adenocarcinoma.