Carnosol suppresses patient-derived gastric tumor growth by targeting RSK2

Area of Science:

• Natural Products Chemistry
• Molecular Oncology
• Pharmacology

Background:

• Carnosol, a phenolic diterpene from rosemary and sage, exhibits antioxidant, anti-inflammatory, and anti-cancer effects.
• The precise molecular mechanisms underlying carnosol's anti-gastric cancer activity remain largely unexplored.
• Investigating novel therapeutic agents for gastric cancer is crucial due to its significant global health impact.

Purpose of the Study:

• To elucidate the molecular mechanism by which carnosol exerts its anti-cancer effects in gastric cancer.
• To identify carnosol as a potential inhibitor of RSK2 (Ribosomal S6 Kinase 2) and its role in gastric cancer.
• To evaluate the therapeutic potential of carnosol against gastric cancer growth both in vitro and in vivo.

Main Methods:

• In vitro screening and cell-based assays were employed to assess carnosol's effects on gastric cancer cells.
• RSK2 activity, downstream signaling pathways (RSKs-CREB), cell cycle progression, and apoptosis were analyzed.
• Patient-derived gastric tumors were utilized in an in vivo mouse model to evaluate carnosol's efficacy upon oral administration.

Main Results:

• Carnosol was identified as an inhibitor of RSK2, effectively repressing its activity and downstream signaling.
• Carnosol significantly reduced both anchorage-dependent and -independent gastric cancer cell growth.
• The compound altered cell cycle distribution (increased G2/M phase, decreased S phase) and induced apoptosis via caspase activation and Bcl-xL inhibition.
• Oral administration of carnosol suppressed the growth of patient-derived gastric tumors in vivo.

Conclusions:

• Carnosol functions as an RSK2 inhibitor, demonstrating significant anti-gastric cancer properties.
• The RSKs-CREB signaling pathway is a key target for carnosol's inhibitory effects on gastric cancer growth.
• Carnosol presents a promising therapeutic candidate for the treatment of gastric cancer, warranting further clinical investigation.