Molecular pathways: harnessing E2F1 regulation for prosenescence therapy in p53-defective cancer cells.
Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies.
Authors' Affiliations: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University; and.
Anni
A
Laine
Authors' Affiliations: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University; and Department of Pathology, University of Turku, Turku, Finland jukka.westermarck@utu.fi.
Jukka
J
Westermarck
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016922:Cellular Senescence; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53