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Article: Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma

TitleBlocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma
Authors
KeywordsCancer stem cells
CDK1 inhibitor
Hepatocellular carcinoma
PDX models
RO3306
Sorafenib
Issue Date2018
PublisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/
Citation
Theranostics, 2018, v. 8 n. 14, p. 3737-3750 How to Cite?
AbstractRationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.
Persistent Identifierhttp://hdl.handle.net/10722/259527
ISSN
2023 Impact Factor: 12.4
2023 SCImago Journal Rankings: 2.912
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWu, C-
dc.contributor.authorWang, X-
dc.contributor.authorChok, KSH-
dc.contributor.authorMan, K-
dc.contributor.authorTsang, HYS-
dc.contributor.authorChan, ACY-
dc.contributor.authorMa, KW-
dc.contributor.authorXia, W-
dc.contributor.authorCheung, TT-
dc.date.accessioned2018-09-03T04:09:22Z-
dc.date.available2018-09-03T04:09:22Z-
dc.date.issued2018-
dc.identifier.citationTheranostics, 2018, v. 8 n. 14, p. 3737-3750-
dc.identifier.issn1838-7640-
dc.identifier.urihttp://hdl.handle.net/10722/259527-
dc.description.abstractRationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.-
dc.languageeng-
dc.publisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/-
dc.relation.ispartofTheranostics-
dc.rightsTheranostics. Copyright © Ivyspring International Publisher.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCancer stem cells-
dc.subjectCDK1 inhibitor-
dc.subjectHepatocellular carcinoma-
dc.subjectPDX models-
dc.subjectRO3306-
dc.subjectSorafenib-
dc.titleBlocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailWang, X: xqwang@hku.hk-
dc.identifier.emailChok, KSH: chok6275@hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailChan, ACY: acchan@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.authorityWang, X=rp00507-
dc.identifier.authorityChok, KSH=rp02110-
dc.identifier.authorityMan, K=rp00417-
dc.identifier.authorityChan, ACY=rp00310-
dc.identifier.authorityCheung, TT=rp02129-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7150/thno.25487-
dc.identifier.pmid30083256-
dc.identifier.pmcidPMC6071527-
dc.identifier.scopuseid_2-s2.0-85049168523-
dc.identifier.hkuros288568-
dc.identifier.volume8-
dc.identifier.issue14-
dc.identifier.spage3737-
dc.identifier.epage3750-
dc.identifier.isiWOS:000440376700002-
dc.publisher.placeAustralia-
dc.identifier.issnl1838-7640-

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