title: CDK4 inhibitors and apoptosis: a novel mechanism requiring nucleolar targeting of RelA.
abstract: Components of the cyclin D-CDK4/6-INK4-Rb pathway are key regulators of the cell cycle and are frequently disrupted in cancer. Defects in this pathway usually manifest as an increase in CDK4 activity, leading to unrestricted proliferation of tumour cells. CDK4 inhibitors have been shown to possess anti-tumour activity in vitro and agents that target the cyclin D1/CDK4 complex are currently the focus of intense scrutiny for clinical application as cancer therapeutics. However, the mechanisms by which these agents mediate their effects remains to be fully elucidated. We recently described a novel mechanism by which a CDK4 inhibitor induces apoptosis in colon cancer cells through activation of the NFkB signaling pathway. Specific inhibition of CDK4 activity induced translocation of RelA, the principal component of NFkappaB, from the cytoplasm to the nucleoplasm and then to the nucleolus. This was accompanied by a repression of NFkappaB-driven transcription and apoptosis of the cancer cells. To determine the role of RelA in apoptosis, we utilised a mutant form of the protein, where the critical domain required for nucleolar targeting had been deleted. When cells expressing this mutant protein were treated with the CDK4 inhibitor, RelA translocated from the cytoplasm to the nucleoplasm, but was excluded from the nucleolus. Furthermore, apoptosis induced by CDK4 inhibition was also abrogated in cells expressing mutant RelA protein. Here, we discuss the molecular mechanisms that regulate programmed cell death induced by disruption of the cyclin D1/CDK4 complex and consider the wider implications these findings have for the future development of novel chemotherapeutic agents.
authors.affiliation: Colon Cancer Genetics Group, Edinburgh Cancer Research Centre, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK. h.thoms@hgu.mrc.ac.uk
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Thoms
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Stark
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism; D002466:Cell Nucleolus / Q000378:metabolism*; D017321:Clinical Trials, Phase I as Topic; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D016213:Cyclins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051996:Transcription Factor RelA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C521501:2-bromo-12,13-dihydro-5-indolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6H)-dione; D000970:Antineoplastic Agents; D002227:Carbazoles; D056741:Cyclin D; D016213:Cyclins; D007211:Indoles; D016328:NF-kappa B; D010879:Piperazines; D011725:Pyridines; C498143:RELA protein, human; D051996:Transcription Factor RelA; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib