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      • Record: found
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      Treating cancer when pRb and p53 cannot be reactivated

      research-article
      Author(s): *
      Publication date (Electronic):
      Journal: Molecular & Cellular Oncology
      Publisher: Taylor & Francis
      Keywords: cancer therapy, genetic inactivation, miR-17-92, pRb, p53, Skp2

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          Abstract

          Activation of oncoproteins and inactivation of tumor suppressors induces tumorigenesis. When these events happen upstream of pRb and p53, cancer therapies may initially succeed and then fail when pRb and p53 are activated and then re-inactivated. Therapies might succeed if they remain effective when pRb and p53 are genetically inactivated.

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          Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.

          Ainara Egia, K. S. Nakayama, Guocan Wang … (2010)
          Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19(Arf)-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19(Arf)-p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.
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            Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice.

            Rani S. Sellers, Jessica D Sun, David Cobrinik … (2009)
            Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied retinoblastoma protein (pRb) targets partially inhibited tumorigenesis in Rb1(+/-) mice. Here we report that inactivation of pRb target Skp2 (refs. 7,8) completely prevents spontaneous tumorigenesis in Rb1(+/-) mice. Targeted Rb1 deletion in melanotrophs ablates the entire pituitary intermediate lobe when Skp2 is inactivated. Skp2 inactivation does not inhibit aberrant proliferation of Rb1-deleted melanotrophs but induces their apoptotic death. Eliminating p27 phosphorylation on T187 in p27T187A knock-in mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCF(Skp2) ubiquitin ligase as the underlying mechanism for Skp2's essential tumorigenic role in this setting. RB1-deficient human retinoblastoma cells also undergo apoptosis after Skp2 knockdown; and ectopic expression of p27, especially the p27T187A mutant, induces apoptosis. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb1 deficiency.
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              Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors.

              Shi-Liang Zhu, Gottfried J Locker, Frederick Bauzon … (2013)
              pRb and p53 are two major tumor suppressors. Here, we found that p53 activates expression of Pirh2 and KPC1, two of the three ubiquitin ligases for p27. Loss of p53 in the absence of Skp2, the third ubiquitin ligase for p27, shrinks the cellular pool of p27 ubiquitin ligases to accumulate p27 protein. In the absence of pRb and p53, p27 was unable to inhibit DNA synthesis in spite of its abundance, but could inhibit division of cells that maintain DNA replication with rereplication. This mechanism blocked pRb/p53 doubly deficient pituitary and prostate tumorigenesis lastingly coexistent with bromodeoxyuridine-labeling neoplastic lesions, revealing an unconventional cancer cell vulnerability when pRb and p53 are inactivated. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Cell Oncol
                Journal ID (iso-abbrev): Mol Cell Oncol
                Journal ID (pmc): KMCO
                Title: Molecular & Cellular Oncology
                Publisher: Taylor & Francis
                ISSN (Electronic): 2372-3556
                Publication date Collection: Oct-Dec 2015
                Publication date (Electronic): 5 May 2015
                Volume: 2
                Issue: 4
                Electronic Location Identifier: e1004954
                Affiliations
                Department of Developmental & Molecular Biology, and Ophthalmology & Visual Sciences, and Medicine; The Albert Einstein Comprehensive Cancer Center and Liver Research Center; Albert Einstein College of Medicine ; Bronx, NY, USA
                Author notes
                [* ]Corresponding to: Liang Zhu; Email: liang.zhu@ 123456einstein.yu.edu
                Article
                Publisher ID: 1004954
                DOI: 10.1080/23723556.2015.1004954
                PMC ID: 4905341
                PubMed ID: 27308498
                SO-VID: d01d2c6b-39ee-4cc8-8497-3f87427f349e
                Copyright © © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 23 December 2014
                Date revision received : 24 December 2014
                Date accepted : 25 December 2014
                Page count
                Figures: 1, Tables: 0, References: 10, Pages: 3
                Categories
                Subject: Author's View

                Keywords: cancer therapy,genetic inactivation,mir-17-92,prb,p53,skp2
                Data availability:
                Keywords: cancer therapy, genetic inactivation, mir-17-92, prb, p53, skp2

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