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      NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction

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          Abstract

          NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.

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          PI3K signalling: the path to discovery and understanding.

          Bart Vanhaesebroeck, Len Stephens, Phillip N Hawkins (2012)
          Over the past two decades, our understanding of phospoinositide 3-kinases (PI3Ks) has progressed from the identification of an enzymatic activity associated with growth factors, GPCRs and certain oncogene products to a disease target in cancer and inflammation, with PI3K inhibitors currently in clinical trials. Elucidation of PI3K-dependent networks led to the discovery of the phosphoinositide-binding PH, PX and FYVE domains as conduits of intracellular lipid signalling, the determination of the molecular function of the tumour suppressor PTEN and the identification of AKT and mTOR protein kinases as key regulators of cell growth. Here we look back at the main discoveries that shaped the PI3K field.
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            PUMA, a novel proapoptotic gene, is induced by p53.

            K Nakano, K Vousden (2001)
            The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named PUMA (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (PUMA-alpha and PUMA-beta) that are induced in cells following p53 activation. PUMA-alpha and PUMA-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
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              PUMA, a potent killer with or without p53.

              J. Yu, L. Zhang (2008)
              PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a critical mediator of p53-dependent and -independent apoptosis induced by a wide variety of stimuli, including genotoxic stress, deregulated oncogene expression, toxins, altered redox status, growth factor/cytokine withdrawal and infection. It serves as a proximal signaling molecule whose expression is regulated by transcription factors in response to these stimuli. PUMA transduces death signals primarily to the mitochondria, where it acts indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members. It directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. PUMA ablation or inhibition leads to apoptosis deficiency underlying increased risks for cancer development and therapeutic resistance. Although elevated PUMA expression elicits profound chemo- and radiosensitization in cancer cells, inhibition of PUMA expression may be useful for curbing excessive cell death associated with tissue injury and degenerative diseases. Therefore, PUMA is a general sensor of cell death stimuli and a promising drug target for cancer therapy and tissue damage.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 10 October 2017
                Publication date (Electronic): 15 September 2017
                Volume: 8
                Issue: 47
                Pages: 83052-83062
                Affiliations
                1 Department of Laboratory Medicine, The People’s Hospital of Liaoning Province, Shenyang, China
                2 Department of Anesthesia, The People’s Hospital of Liaoning Province, Shenyang, China
                3 Department of Gynaecology and Obstetrics, The People’s Hospital of Liaoning Province, Shenyang, China
                4 Department of Ultrasound Diagnosis, The People’s Hospital of Liaoning Province, Shenyang, China
                5 Department of Neurology, The People’s Hospital of Liaoning Province, Shenyang, China
                Author notes
                Correspondence to: Hongmei Zhao, yangshidasy@ 123456gmail.com
                Article
                Publisher ID: 20943
                DOI: 10.18632/oncotarget.20943
                PMC ID: 5669949
                PubMed ID: 29137323
                SO-VID: 2237e2e6-eaaf-49b8-ba8f-f6ca4f0aaf68
                Copyright © Copyright: © 2017 Yang et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 9 May 2017
                Date accepted : 26 July 2017
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: nvp-bkm120,puma,apoptosis,foxo3a,colon cancer
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: nvp-bkm120, puma, apoptosis, foxo3a, colon cancer

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