Carfilzomib activates ER stress and JNK/p38 MAPK signaling to promote apoptosis in hepatocellular carcinoma cells

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer death, often diagnosed late with limited treatment options.
• Drug repurposing offers a faster, cost-effective approach to developing new cancer therapies.
• Carfilzomib (CFZ), a proteasome inhibitor, shows efficacy in multiple myeloma and potential in other cancers, but its mechanism in HCC is unknown.

Purpose of the Study:

• To investigate the anti-cancer mechanisms of Carfilzomib (CFZ) in Hepatocellular carcinoma (HCC) cells.
• To evaluate the therapeutic potential of CFZ as a repurposed drug for HCC treatment.

Main Methods:

• Cell proliferation, migration, and invasion assays were performed on HCC cell lines treated with CFZ.
• Mechanisms including cell cycle analysis, epithelial-mesenchymal transition (EMT) markers, reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and JNK/p38 MAPK signaling were assessed.
• In vivo efficacy was evaluated using a HCC xenograft mouse model.

Main Results:

• CFZ inhibited HCC cell proliferation by inducing G2/M phase cell cycle arrest.
• CFZ suppressed HCC cell migration and invasion by inhibiting EMT.
• CFZ treatment increased ROS production, leading to ER stress and activation of JNK/p38 MAPK signaling, ultimately inducing HCC cell death.
• CFZ significantly reduced tumor growth in a xenograft mouse model.

Conclusions:

• CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling pathways in HCC cells.
• These mechanisms contribute to the inhibition of HCC cell proliferation and tumor growth.
• CFZ demonstrates significant potential as an effective therapeutic agent for Hepatocellular carcinoma.