Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/p-catenin pathway in xenograft models of hepatocellular carcinoma
Mutations affecting the Wnt/[beta]-catenin pathway have been identified in 26-40% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/p-catenin pathway inhibitors may benefit a subset of patients wi...
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| Veröffentlicht in: | International journal of oncology 2019-03, Vol.54 (3), p.1123 |
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| container_title | International journal of oncology |
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| creator | Huynh, Hung Ong, Richard Goh, Kah Yong Lee, Liek Yeow Puehler, Florian Scholz, Arne Politz, Oliver Mumberg, Dominik Ziegelbauer, Karl |
| description | Mutations affecting the Wnt/[beta]-catenin pathway have been identified in 26-40% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/p-catenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/[beta]-catenin signaling in HCC models were evaluated. A [beta]-catenin mutant and [beta]-catenin wild-type HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/[beta]-catenin signaling. Apoptosis, cell proliferation and [beta]-catenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naive and sorafenib-resistant HCC models. Despite similar total [beta]-catenin levels, significant reductions in phosphorylated (p)-RanBP3 Ser58, p-[beta]-catenin Tyr142, active [beta]-catenin and [beta]-catenin target genes were observed in sorafenib/refametinib-treated tumors. Greater levels of [beta]-catenin in sorafenib/refametinib-treated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/[beta]-catenin pathway and suppressed Wnt-3A-induced p-low-density lipoprotein receptor-related protein 6 Ser1490, p-RanBP3 Ser58 and p-[beta]-catenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naive and sorafenib resistant HCC tumors in association with active suppression of [beta]-catenin signaling regardless of [beta]-catenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy. Key words: Wnt/p-catenin pathway, patient-derived xenograft, hepatocellular carcinoma, sorafenib, MEK inhibitor, refametinib, selumetinib |
| doi_str_mv | 10.3892/ijo.2019.4693 |
| format | Article |
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Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/p-catenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/[beta]-catenin signaling in HCC models were evaluated. A [beta]-catenin mutant and [beta]-catenin wild-type HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/[beta]-catenin signaling. Apoptosis, cell proliferation and [beta]-catenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naive and sorafenib-resistant HCC models. Despite similar total [beta]-catenin levels, significant reductions in phosphorylated (p)-RanBP3 Ser58, p-[beta]-catenin Tyr142, active [beta]-catenin and [beta]-catenin target genes were observed in sorafenib/refametinib-treated tumors. Greater levels of [beta]-catenin in sorafenib/refametinib-treated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/[beta]-catenin pathway and suppressed Wnt-3A-induced p-low-density lipoprotein receptor-related protein 6 Ser1490, p-RanBP3 Ser58 and p-[beta]-catenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naive and sorafenib resistant HCC tumors in association with active suppression of [beta]-catenin signaling regardless of [beta]-catenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy. Key words: Wnt/p-catenin pathway, patient-derived xenograft, hepatocellular carcinoma, sorafenib, MEK inhibitor, refametinib, selumetinib</description><identifier>ISSN: 1019-6439</identifier><identifier>DOI: 10.3892/ijo.2019.4693</identifier><language>eng</language><publisher>Spandidos Publications</publisher><subject>Analysis ; Biological markers ; Cancer ; Carcinoma ; Cell death ; Combination chemotherapy ; Development and progression ; Drug therapy ; EDTA ; Enzyme inhibitors ; Gene mutation ; Genes ; Genetic aspects ; Health aspects ; Hepatocellular carcinoma ; Immunohistochemistry ; Low density lipoproteins ; Methods ; Patient outcomes ; Regorafenib ; Sorafenib ; Tumors</subject><ispartof>International journal of oncology, 2019-03, Vol.54 (3), p.1123</ispartof><rights>COPYRIGHT 2019 Spandidos Publications</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Huynh, Hung</creatorcontrib><creatorcontrib>Ong, Richard</creatorcontrib><creatorcontrib>Goh, Kah Yong</creatorcontrib><creatorcontrib>Lee, Liek Yeow</creatorcontrib><creatorcontrib>Puehler, Florian</creatorcontrib><creatorcontrib>Scholz, Arne</creatorcontrib><creatorcontrib>Politz, Oliver</creatorcontrib><creatorcontrib>Mumberg, Dominik</creatorcontrib><creatorcontrib>Ziegelbauer, Karl</creatorcontrib><title>Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/p-catenin pathway in xenograft models of hepatocellular carcinoma</title><title>International journal of oncology</title><description>Mutations affecting the Wnt/[beta]-catenin pathway have been identified in 26-40% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/p-catenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/[beta]-catenin signaling in HCC models were evaluated. A [beta]-catenin mutant and [beta]-catenin wild-type HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/[beta]-catenin signaling. Apoptosis, cell proliferation and [beta]-catenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naive and sorafenib-resistant HCC models. Despite similar total [beta]-catenin levels, significant reductions in phosphorylated (p)-RanBP3 Ser58, p-[beta]-catenin Tyr142, active [beta]-catenin and [beta]-catenin target genes were observed in sorafenib/refametinib-treated tumors. Greater levels of [beta]-catenin in sorafenib/refametinib-treated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/[beta]-catenin pathway and suppressed Wnt-3A-induced p-low-density lipoprotein receptor-related protein 6 Ser1490, p-RanBP3 Ser58 and p-[beta]-catenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naive and sorafenib resistant HCC tumors in association with active suppression of [beta]-catenin signaling regardless of [beta]-catenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy. Key words: Wnt/p-catenin pathway, patient-derived xenograft, hepatocellular carcinoma, sorafenib, MEK inhibitor, refametinib, selumetinib</description><subject>Analysis</subject><subject>Biological markers</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Cell death</subject><subject>Combination chemotherapy</subject><subject>Development and progression</subject><subject>Drug therapy</subject><subject>EDTA</subject><subject>Enzyme inhibitors</subject><subject>Gene mutation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hepatocellular carcinoma</subject><subject>Immunohistochemistry</subject><subject>Low density lipoproteins</subject><subject>Methods</subject><subject>Patient outcomes</subject><subject>Regorafenib</subject><subject>Sorafenib</subject><subject>Tumors</subject><issn>1019-6439</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptkE9LxDAQxXNQcF09eg8I3tpN2qZNj8uy_sEVDy54XCZp0mZJk6XNsvoJ_NpGVFhB5jDDm997A4PQFSVpzutsZrY-zQit06Ks8xM0oXFOyiKvz9D5OG4JyRgjdII-XvwAWjkjZk_LR2xcZ4QJfsDS98I4CMa7X3XEYd_HVTv4Q-gwuAaHTuFXF2a7REKIKQ7vIHQHeI8e_Kacb2N6wL1vlB2x17hTEfBSWbu3EK_AII3zPVygUw12VJc_fYrWt8v14j5ZPd89LOarpK05T5TIFWcgqkyIquRacSJko4gupaRUCCgYBUF4VnFVV6xgmknGddbUDaGcQD5F19-xLVi1MU77MIDszSg3c1axnFWk5JFK_6FiNao30julTdT_GG6ODJ0CG7rR2_3X98Zj8BN1QYEh</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Huynh, Hung</creator><creator>Ong, Richard</creator><creator>Goh, Kah Yong</creator><creator>Lee, Liek Yeow</creator><creator>Puehler, Florian</creator><creator>Scholz, Arne</creator><creator>Politz, Oliver</creator><creator>Mumberg, Dominik</creator><creator>Ziegelbauer, Karl</creator><general>Spandidos Publications</general><scope/></search><sort><creationdate>20190301</creationdate><title>Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/p-catenin pathway in xenograft models of hepatocellular carcinoma</title><author>Huynh, Hung ; Ong, Richard ; Goh, Kah Yong ; Lee, Liek Yeow ; Puehler, Florian ; Scholz, Arne ; Politz, Oliver ; Mumberg, Dominik ; Ziegelbauer, Karl</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g988-eb3e85ab72bb768fe80bcde0f6cc11bba451ab08278e97545f5c58f2d9d0180a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Analysis</topic><topic>Biological markers</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Cell death</topic><topic>Combination chemotherapy</topic><topic>Development and progression</topic><topic>Drug therapy</topic><topic>EDTA</topic><topic>Enzyme inhibitors</topic><topic>Gene mutation</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hepatocellular carcinoma</topic><topic>Immunohistochemistry</topic><topic>Low density lipoproteins</topic><topic>Methods</topic><topic>Patient outcomes</topic><topic>Regorafenib</topic><topic>Sorafenib</topic><topic>Tumors</topic><toplevel>online_resources</toplevel><creatorcontrib>Huynh, Hung</creatorcontrib><creatorcontrib>Ong, Richard</creatorcontrib><creatorcontrib>Goh, Kah Yong</creatorcontrib><creatorcontrib>Lee, Liek Yeow</creatorcontrib><creatorcontrib>Puehler, Florian</creatorcontrib><creatorcontrib>Scholz, Arne</creatorcontrib><creatorcontrib>Politz, Oliver</creatorcontrib><creatorcontrib>Mumberg, Dominik</creatorcontrib><creatorcontrib>Ziegelbauer, Karl</creatorcontrib><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huynh, Hung</au><au>Ong, Richard</au><au>Goh, Kah Yong</au><au>Lee, Liek Yeow</au><au>Puehler, Florian</au><au>Scholz, Arne</au><au>Politz, Oliver</au><au>Mumberg, Dominik</au><au>Ziegelbauer, Karl</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/p-catenin pathway in xenograft models of hepatocellular carcinoma</atitle><jtitle>International journal of oncology</jtitle><date>2019-03-01</date><risdate>2019</risdate><volume>54</volume><issue>3</issue><spage>1123</spage><pages>1123-</pages><issn>1019-6439</issn><abstract>Mutations affecting the Wnt/[beta]-catenin pathway have been identified in 26-40% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/p-catenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/[beta]-catenin signaling in HCC models were evaluated. A [beta]-catenin mutant and [beta]-catenin wild-type HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/[beta]-catenin signaling. Apoptosis, cell proliferation and [beta]-catenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naive and sorafenib-resistant HCC models. Despite similar total [beta]-catenin levels, significant reductions in phosphorylated (p)-RanBP3 Ser58, p-[beta]-catenin Tyr142, active [beta]-catenin and [beta]-catenin target genes were observed in sorafenib/refametinib-treated tumors. Greater levels of [beta]-catenin in sorafenib/refametinib-treated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/[beta]-catenin pathway and suppressed Wnt-3A-induced p-low-density lipoprotein receptor-related protein 6 Ser1490, p-RanBP3 Ser58 and p-[beta]-catenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naive and sorafenib resistant HCC tumors in association with active suppression of [beta]-catenin signaling regardless of [beta]-catenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy. Key words: Wnt/p-catenin pathway, patient-derived xenograft, hepatocellular carcinoma, sorafenib, MEK inhibitor, refametinib, selumetinib</abstract><pub>Spandidos Publications</pub><doi>10.3892/ijo.2019.4693</doi></addata></record> |
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| subjects | Analysis Biological markers Cancer Carcinoma Cell death Combination chemotherapy Development and progression Drug therapy EDTA Enzyme inhibitors Gene mutation Genes Genetic aspects Health aspects Hepatocellular carcinoma Immunohistochemistry Low density lipoproteins Methods Patient outcomes Regorafenib Sorafenib Tumors |
| title | Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/p-catenin pathway in xenograft models of hepatocellular carcinoma |
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