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A Novel Erinacine S Derivative from Hericium erinaceus Overcomes Chemoresistance in Colorectal Cancer Cells by Enhancing TRAIL/TNFR1/DR5 Expression through Histone Acetylation

Summary

This study shows that erinacine S, a natural compound from Lion’s Mane mushrooms, can help overcome drug resistance in colorectal cancer cells. The compound works by activating pathways that trigger cancer cell death and by modifying how genes are expressed at the molecular level. In both laboratory experiments and animal models, erinacine S successfully stopped tumor growth and killed resistant cancer cells, suggesting it could be a promising natural treatment for patients with hard-to-treat colorectal cancer.

Background

Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally, with chemoresistance driven by cancer stem cells (CSCs) contributing to poor outcomes. Hericium erinaceus, known as Lion’s Mane mushroom, has demonstrated pharmaceutical potential with various bioactive compounds including erinacine S. The specific mechanisms of erinacine S in overcoming chemoresistance in CRC cells remain unexplored.

Objective

This study investigates the molecular mechanisms by which erinacine S from H. erinaceus mycelium inhibits chemoresistant human colorectal cancer cells and induces apoptosis. The researchers aimed to elucidate how erinacine S enhances expression of death receptors TRAIL, TNFR1, and DR5 through histone acetylation pathways.

Results

Erinacine S significantly induced apoptosis and suppressed aggressiveness of chemoresistant HCT-116/FUR cells in vitro and inhibited tumor growth in vivo. Treatment activated extrinsic apoptosis pathways (TRAIL, TNFR1, DR5, caspase-3), induced G1 cell cycle arrest, and caused histone H3K9K14ac modifications in TRAIL/TNFR1/DR5 promoters via PAK/FAK/p300 pathways. Erinacine S inactivated the CXCR4/PI3K/Akt/HIF-1α pathway while downregulating p-AKT, p-ERK, and NFκB.

Conclusion

Erinacine S demonstrates potent anti-cancer effects against chemoresistant CRC cells both in vitro and in vivo through epigenetic regulation of death receptors and inhibition of survival pathways. These findings support erinacine S as a promising natural agent for clinical therapy of chemoresistant colorectal cancer patients.
  • Published in:International Journal of Medical Sciences,
  • Study Type:In Vitro and In Vivo Experimental Study,
  • Source: 10.7150/ijms.119894, PMID: 41209562
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