Erk phosphorylation reduces the thymoquinone toxicity in human hepatocarcinoma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) remains a major global health challenge.
• Current targeted therapies for HCC have limitations, especially for metastatic disease.
• Nigella sativa Linn. contains thymoquinone (TQ), a compound with potential anti-cancer properties.

Purpose of the Study:

• To investigate the anti-cancer effects of thymoquinone (TQ) on hepatocellular carcinoma (HCC).
• To elucidate the molecular mechanisms underlying TQ's action, focusing on p38 and extracellular signal-regulated kinases (Erk) pathways.
• To evaluate the therapeutic potential of TQ in combination with Erk inhibition in HCC models.

Main Methods:

• In vitro studies using SK-Hep1 cells treated with TQ.
• In vivo studies using HCC-xenograft nude mouse models.
• Assessment of cell death, apoptosis (caspase3 activation, TUNEL assay), and pathway activation (p38, Erk phosphorylation).
• Pharmacological inhibition of p38 and Erk pathways (p38 inhibitor, si-Erk).

Main Results:

• TQ induced cell death and activated p38 and Erk pathways in SK-Hep1 cells.
• TQ-induced cell death was abrogated by p38 inhibition but enhanced by Erk inhibition (si-Erk).
• Co-treatment with TQ and si-Erk significantly increased toxicity via caspase3 activation and TUNEL assay.
• Erk phosphorylation was identified as a mechanism of drug resistance to TQ.
• Erk inhibition improved the therapeutic efficacy of TQ in HCC-xenograft mouse models.

Conclusions:

• Phosphorylation of p38 is a key mediator of TQ-induced apoptosis in HCC cells.
• Phosphorylation of Erk confers resistance to TQ treatment in HCC.
• Combining TQ with Erk inhibition enhances its anti-cancer effects and therapeutic potential for HCC.
• TQ demonstrates significant potential as an anti-HCC agent when administered under conditions that inhibit Erk signaling.