Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma
<h2>Background</h2><p dir="ltr">Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.</p>&l...
محفوظ في:
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| مؤلفون آخرون: | , , , |
| منشور في: |
2019
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| الموضوعات: | |
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إضافة وسم
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| _version_ | 1864513552246636544 |
|---|---|
| author | Sarita Saraswati (7509626) |
| author2 | Abdulqader Alhaider (7509629) Abdelgalil Mohamed Abdelgadir (14153268) Pooja Tanwer (7509635) Hesham M. Korashy (1474849) |
| author2_role | author author author author |
| author_facet | Sarita Saraswati (7509626) Abdulqader Alhaider (7509629) Abdelgalil Mohamed Abdelgadir (14153268) Pooja Tanwer (7509635) Hesham M. Korashy (1474849) |
| author_role | author |
| dc.creator.none.fl_str_mv | Sarita Saraswati (7509626) Abdulqader Alhaider (7509629) Abdelgalil Mohamed Abdelgadir (14153268) Pooja Tanwer (7509635) Hesham M. Korashy (1474849) |
| dc.date.none.fl_str_mv | 2019-10-16T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12964-019-0430-7 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Phloretin_attenuates_STAT-3_activity_and_overcomes_sorafenib_resistance_targeting_SHP-1_mediated_inhibition_of_STAT3_and_Akt_VEGFR2_pathway_in_hepatocellular_carcinoma/21598437 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Chemical sciences Medicinal and biomolecular chemistry Phloretin Sorafenib STAT3 SHP-1 hepatocellular carcinoma |
| dc.title.none.fl_str_mv | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h2>Background</h2><p dir="ltr">Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.</p><h2>Methods</h2><p dir="ltr">Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2<sup>SR</sup>and Huh7SRxenografts. Molecular docking was done with Swiss dock and Auto Dock Vina.</p><h2>Results</h2><p dir="ltr">PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3<sup>Tyr705</sup>level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway.</p><h2>Conclusion</h2><p dir="ltr">Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1–mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1186/s12964-019-0430-7" target="_blank">http://dx.doi.org/10.1186/s12964-019-0430-7</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_fe2ae3e30aad3a59b8611fe0a159b326 |
| identifier_str_mv | 10.1186/s12964-019-0430-7 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598437 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinomaSarita Saraswati (7509626)Abdulqader Alhaider (7509629)Abdelgalil Mohamed Abdelgadir (14153268)Pooja Tanwer (7509635)Hesham M. Korashy (1474849)Biological sciencesBiochemistry and cell biologyChemical sciencesMedicinal and biomolecular chemistryPhloretinSorafenibSTAT3SHP-1hepatocellular carcinoma<h2>Background</h2><p dir="ltr">Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.</p><h2>Methods</h2><p dir="ltr">Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2<sup>SR</sup>and Huh7SRxenografts. Molecular docking was done with Swiss dock and Auto Dock Vina.</p><h2>Results</h2><p dir="ltr">PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3<sup>Tyr705</sup>level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway.</p><h2>Conclusion</h2><p dir="ltr">Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1–mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1186/s12964-019-0430-7" target="_blank">http://dx.doi.org/10.1186/s12964-019-0430-7</a></p>2019-10-16T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12964-019-0430-7https://figshare.com/articles/journal_contribution/Phloretin_attenuates_STAT-3_activity_and_overcomes_sorafenib_resistance_targeting_SHP-1_mediated_inhibition_of_STAT3_and_Akt_VEGFR2_pathway_in_hepatocellular_carcinoma/21598437CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215984372019-10-16T00:00:00Z |
| spellingShingle | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma Sarita Saraswati (7509626) Biological sciences Biochemistry and cell biology Chemical sciences Medicinal and biomolecular chemistry Phloretin Sorafenib STAT3 SHP-1 hepatocellular carcinoma |
| status_str | publishedVersion |
| title | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| title_full | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| title_fullStr | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| title_full_unstemmed | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| title_short | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| title_sort | Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1–mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma |
| topic | Biological sciences Biochemistry and cell biology Chemical sciences Medicinal and biomolecular chemistry Phloretin Sorafenib STAT3 SHP-1 hepatocellular carcinoma |