Uncovering Anticancer Mechanisms of Spiramycin Derivatives Using Transcriptomic and Metabolomic Analyses

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Carrimycin, a spiramycin derivative mixture, shows potential anticancer activity.
• The precise anticancer mechanism of carrimycin remains largely unknown.
• Spiramycin derivatives are primarily known for their antibacterial functions.

Purpose of the Study:

• To elucidate the anticancer mechanism of carrimycin.
• To investigate the effects of n-hexyl spiramycin (h-SPM), a synthesized derivative, on cancer cells.
• To identify key molecular pathways involved in h-SPM's anticancer effects.

Main Methods:

• Combined metabolomics (CE-MS, LC-MS) and transcriptomics analyses.
• Synthesis of n-hexyl spiramycin (h-SPM).
• Bioinformatic processing of multi-omics data.
• Western blotting, ROS staining, and quantitative PCR (qPCR) for validation.

Main Results:

• h-SPM treatment altered lipid metabolism and mitochondrial biogenesis pathways.
• Enrichment of NR1D1 genes and ceramide was observed, suggesting roles for ROS and inflammation.
• Decreased NR1D1 protein levels, elevated ROS, and induced pro-inflammatory gene expression confirmed h-SPM's impact.

Conclusions:

• h-SPM disrupts cellular metabolic regulation and reduces NR1D1 protein levels.
• Accumulation of ceramide and subsequent ROS generation promote apoptosis and pro-inflammatory responses.
• This study reveals the anticancer mechanism of a potent spiramycin derivative, h-SPM.