Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo
<p dir="ltr">Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palboc...
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2019
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| _version_ | 1864513520773627904 |
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| author | Ramesh Elango (7542068) |
| author2 | Radhakrishnan Vishnubalaji (3563306) Muthurangan Manikandan (6002243) Sarah Ibrahim Binhamdan (18619234) Abdul-Aziz Siyal (18619237) Yasser A. Alshawakir (13730570) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Nehad M. Alajez (7397276) |
| author2_role | author author author author author author author author |
| author_facet | Ramesh Elango (7542068) Radhakrishnan Vishnubalaji (3563306) Muthurangan Manikandan (6002243) Sarah Ibrahim Binhamdan (18619234) Abdul-Aziz Siyal (18619237) Yasser A. Alshawakir (13730570) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Nehad M. Alajez (7397276) |
| author_role | author |
| dc.creator.none.fl_str_mv | Ramesh Elango (7542068) Radhakrishnan Vishnubalaji (3563306) Muthurangan Manikandan (6002243) Sarah Ibrahim Binhamdan (18619234) Abdul-Aziz Siyal (18619237) Yasser A. Alshawakir (13730570) Musaad Alfayez (3571736) Abdullah Aldahmash (3563300) Nehad M. Alajez (7397276) |
| dc.date.none.fl_str_mv | 2019-09-23T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-019-50140-0 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Concurrent_targeting_of_BMI1_and_CDK4_6_abrogates_tumor_growth_in_vitro_and_in_vivo/25908364 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis Cancer management Therapy resistance Cytotoxic medications Combination-based treatment regimens PTC-209 Palbociclib BMI1 protein expression |
| dc.title.none.fl_str_mv | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRb<sup>Ser795</sup> protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-019-50140-0" target="_blank">https://dx.doi.org/10.1038/s41598-019-50140-0</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_4d90751d7a0ad8f48fb158c4767930be |
| identifier_str_mv | 10.1038/s41598-019-50140-0 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25908364 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivoRamesh Elango (7542068)Radhakrishnan Vishnubalaji (3563306)Muthurangan Manikandan (6002243)Sarah Ibrahim Binhamdan (18619234)Abdul-Aziz Siyal (18619237)Yasser A. Alshawakir (13730570)Musaad Alfayez (3571736)Abdullah Aldahmash (3563300)Nehad M. Alajez (7397276)Biomedical and clinical sciencesOncology and carcinogenesisCancer managementTherapy resistanceCytotoxic medicationsCombination-based treatment regimensPTC-209PalbociclibBMI1 protein expression<p dir="ltr">Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRb<sup>Ser795</sup> protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-019-50140-0" target="_blank">https://dx.doi.org/10.1038/s41598-019-50140-0</a></p>2019-09-23T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-019-50140-0https://figshare.com/articles/journal_contribution/Concurrent_targeting_of_BMI1_and_CDK4_6_abrogates_tumor_growth_in_vitro_and_in_vivo/25908364CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259083642019-09-23T03:00:00Z |
| spellingShingle | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo Ramesh Elango (7542068) Biomedical and clinical sciences Oncology and carcinogenesis Cancer management Therapy resistance Cytotoxic medications Combination-based treatment regimens PTC-209 Palbociclib BMI1 protein expression |
| status_str | publishedVersion |
| title | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| title_full | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| title_fullStr | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| title_full_unstemmed | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| title_short | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| title_sort | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis Cancer management Therapy resistance Cytotoxic medications Combination-based treatment regimens PTC-209 Palbociclib BMI1 protein expression |