Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes.
Inducing an apoptotic response is the goal of most current chemotherapeutic interventions against cancer. However, little is known about the effect of chemotherapeutic agents on the alternative splicing of apoptotic genes. Here, we have tested 20 of the mainstream anticancer drugs for their ability to influence the production of Bcl-x splice isoforms. We find that many drugs shift splicing toward the proapoptotic Bcl-x(S) splice variant in 293 cells. The drugs modulate splicing decisions most likely through signaling events because the splicing switch is not compromised by inhibiting de novo protein synthesis or the activity of caspases. Several drugs also shift Bcl-x splicing in cancer cell lines (MCF-7, HeLa, PC-3, PA-1, and SKOV-3), but the set of active drugs varies between cell lines. We also examined the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes in different cell lines. Almost every drug can alter a subset of alternative splicing events in each cell line. Although drugs of the same class often influence the alternative splicing of the same units in individual cell lines, these units differ considerably between cell lines, indicating cell line-specific differences in the pathways that control splicing.
Shkreta
Lulzim
L
Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, Quebec, Canada.
Froehlich
Ulrike
U
Paquet
Eric R
ER
Toutant
Johanne
J
Elela
Sherif Abou
SA
Chabot
Benoit
B
D017398:Alternative Splicing / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects; D051020:bcl-X Protein / Q000235:genetics*
D000970:Antineoplastic Agents; D051020:bcl-X Protein; D020169:Caspases