Ancistrocladinium A induces cell death in drug-resistant myeloma cells via targeting transcription and RNA splicing machinery and ATF4-dependent apoptotic pathway: a promising candidate as a drug for multiple myeloma

ABSTRACT: N,C-coupled naphthylisoquinoline alkaloids like the natural product ancistrocladinium A, was known for its strong antiprotozoal activity, but had never explored for its antitumor activity. We found the alkaloid to be a very efficient anti-myeloma agent in various cell lines, including proteasome inhibitor-resistant cell lines and patient's primary CD138+ myeloma cells either alone or in combination approaches with the compounds carfilzomib or panobinostat. To gain further insight, we used an MS-based approach with the biotinylated derivative of Ancistrocladinium A, leading to an enrichment of RNA splicing associated proteins. We validated alternative pre-mRNA splicing by analyzing RNA gene expression and splicing using the human Clariom D gene array after treatment of INA-6 cells with the alkaloid. Important pathways with altered RNA expression levels included RNA processing, transcription and splicing, and the ribonucleoprotein complex. Pathways with altered RNA splicing included PSMB5 target genes and, therefore, a driver of unfolded protein response (UPR) along with transcription-associated and cell cycle-associated genes. Furthermore, we confirmed the splicing-induced protein expression of activating tran-scription factor 4 (ATF4), a key regulator of UPR. Finally, histone 2A (H2A) phosphorylation and PARP-1 cleavage as an indicator of apoptosis indicator was also detected. Taken together, an-cistrocladinium A can be considered as a potent agent against PI-resistance in MM either alone or in combination with clinically approved drugs.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: Daniela Bruennert  

LAB HEAD: Manik Chatterjee

PROVIDER: PXD043261 | Pride | 2023-10-24

REPOSITORIES: Pride