Sorafenib inhibits cancer side population cells by targeting c‑Jun N‑terminal kinase signaling

Area of Science:

• Oncology
• Cancer Stem Cell Research
• Molecular Biology

Background:

• Advanced hepatocellular carcinoma (HCC) remains a significant clinical challenge.
• Cancer stem cells (CSCs) are implicated in tumor recurrence and drug resistance.
• Sorafenib is a standard systemic therapy for advanced HCC.

Purpose of the Study:

• To evaluate the anticancer effects of sorafenib on hepatocellular carcinoma stem cell-like (SP) cells.
• To investigate the role of c-Jun N-terminal kinase (JNK) signaling in sorafenib resistance.
• To analyze the impact of sorafenib on CSC properties in HCC models.

Main Methods:

• Huh7 and Huh-BAT HCC cell lines were treated with sorafenib, 5-fluorouracil (5-FU), or combination therapy.
• Evaluated were cell growth rates, side population (SP) fraction, and sphere-forming efficacy.
• Assessed expression levels of JNK signaling pathway molecules.

Main Results:

• Both sorafenib and 5-FU reduced overall cell growth but had differential effects on SP cells.
• 5-FU increased SP cell numbers and upregulated JNK signaling.
• Sorafenib decreased SP cell numbers and downregulated JNK signaling, without affecting sphere formation.
• Sorafenib demonstrated anticancer effects in HCC and SP cells by targeting JNK signaling.

Conclusions:

• Sorafenib exhibits potent anticancer activity against HCC, including cancer stem cell-like populations.
• Targeting the JNK signaling pathway is a key mechanism for sorafenib's efficacy in HCC.
• Sorafenib represents a promising therapeutic strategy for overcoming drug resistance in advanced HCC.