Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4
<p>Abstract</p> <p>Background</p> <p>Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appr...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2011-06-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | http://www.molecular-cancer.com/content/10/1/72 |
| _version_ | 1818360351098404864 |
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| author | Agarwala Usha Blaydes Jeremy P Maurer Richard I Essex Jon W Kilburn Jeremy D Warenius Hilmar M Seabra Laurence A |
| author_facet | Agarwala Usha Blaydes Jeremy P Maurer Richard I Essex Jon W Kilburn Jeremy D Warenius Hilmar M Seabra Laurence A |
| author_sort | Agarwala Usha |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, <it>CDK4 </it>gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of <it>CDK2 </it>and <it>CDK6</it>; and <it>o</it>verexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor.</p> <p>Results</p> <p>A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy.</p> <p>Conclusion</p> <p>These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.</p> |
| first_indexed | 2024-12-13T20:59:24Z |
| format | Article |
| id | doaj.art-831baca1336543f8860c722d104c6ede |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-13T20:59:24Z |
| publishDate | 2011-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-831baca1336543f8860c722d104c6ede2022-12-21T23:31:38ZengBMCMolecular Cancer1476-45982011-06-011017210.1186/1476-4598-10-72Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4Agarwala UshaBlaydes Jeremy PMaurer Richard IEssex Jon WKilburn Jeremy DWarenius Hilmar MSeabra Laurence A<p>Abstract</p> <p>Background</p> <p>Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, <it>CDK4 </it>gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of <it>CDK2 </it>and <it>CDK6</it>; and <it>o</it>verexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor.</p> <p>Results</p> <p>A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy.</p> <p>Conclusion</p> <p>These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.</p>http://www.molecular-cancer.com/content/10/1/72Cdk4non-kinaseproteomicPRGPRPprogrammed cell deathselective anticancerbroad spectrum |
| spellingShingle | Agarwala Usha Blaydes Jeremy P Maurer Richard I Essex Jon W Kilburn Jeremy D Warenius Hilmar M Seabra Laurence A Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 Molecular Cancer Cdk4 non-kinase proteomic PRGPRP programmed cell death selective anticancer broad spectrum |
| title | Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 |
| title_full | Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 |
| title_fullStr | Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 |
| title_full_unstemmed | Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 |
| title_short | Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4 |
| title_sort | selective anticancer activity of a hexapeptide with sequence homology to a non kinase domain of cyclin dependent kinase 4 |
| topic | Cdk4 non-kinase proteomic PRGPRP programmed cell death selective anticancer broad spectrum |
| url | http://www.molecular-cancer.com/content/10/1/72 |
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