Acute sensitization of colon cancer cells to inflammatory cytokines by prophase arrest.
Understanding how colon cancer cells survive within the inflammatory milieu of a tumor, and developing approaches that increase their sensitivity to inflammatory cytokines, may ultimately lead to novel approaches for colon cancer therapy and prevention. Analysis of a number of chemopreventive and therapeutic agents reveal that HDAC inhibitors are particularly adept at sensitizing colon cancer cells TNF or TRAIL mediated apoptosis. In vivo data are consistent with an interaction between SAHA and TNF in inducing apoptosis, as AOM-induced colon tumors express elevated levels of TNF and are more sensitive to SAHA administration. Cell cycle analysis and time-lapse imaging indicated a close correspondence between SAHA-induced prophase arrest and TNF or TRAIL-induced apoptosis. Prophase arrest induced by the Aurora kinase inhibitor VX680 likewise sensitized cells to TNF and TRAIL, with siRNA analysis pointing to Aurora kinase A (and not Aurora kinase B) as being the relevant target for this sensitization. We propose that agents that promote prophase arrest may help sensitize cancer cells to TNF and other inflammatory cytokines. We also discuss how circumvention of an early mitotic checkpoint may facilitate cancer cell survival in the inflammatory micro-environment of the tumor.
Department of Molecular and Cell Biology, 91 North Eagleville Road, University of Connecticut, Storrs, CT 06269, United States.
Anton
A
Kuratnik
Virginia E
VE
Senapati
Rajeev
R
Verma
Barbara G
BG
Mellone
Anthony T
AT
Vella
Charles
C
Giardina
D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002087:Butyrates / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000494:pharmacology; D011418:Prophase / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002087:Butyrates; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576917:AURKA protein, human; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse