MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK

Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of live...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Zhai, Beibei [verfasserIn] Zhang, Xiaofeng Sun, Bin Cao, Lu Zhao, Linlin Li, Jun Ge, Naijian Chen, Lei Qian, Haihua Yin, Zhengfeng

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	Hepatocellular carcinoma Liver cancer stem cells Sorafenib MK2206

Anmerkung:	© International Society of Oncology and BioMarkers (ISOBM) 2015

Übergeordnetes Werk:	Enthalten in: Tumor biology - Amsterdam : IOS Press, 1987, 37(2015), 6 vom: 28. Dez., Seite 8047-8055
Übergeordnetes Werk:	volume:37 ; year:2015 ; number:6 ; day:28 ; month:12 ; pages:8047-8055

Links:	Volltext

DOI / URN:	10.1007/s13277-015-4707-1

Katalog-ID:	SPR031175317

Internformat


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520			\|a Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib.
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allfields	10.1007/s13277-015-4707-1 doi (DE-627)SPR031175317 (SPR)s13277-015-4707-1-e DE-627 ger DE-627 rakwb eng Zhai, Beibei verfasserin aut MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213 Zhang, Xiaofeng aut Sun, Bin aut Cao, Lu aut Zhao, Linlin aut Li, Jun aut Ge, Naijian aut Chen, Lei aut Qian, Haihua aut Yin, Zhengfeng (orcid)0000-0001-6203-9507 aut Enthalten in Tumor biology Amsterdam : IOS Press, 1987 37(2015), 6 vom: 28. Dez., Seite 8047-8055 (DE-627)300897855 (DE-600)1483579-4 1423-0380 nnns volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055 https://dx.doi.org/10.1007/s13277-015-4707-1 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_22 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_63 GBV_ILN_95 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_370 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4338 AR 37 2015 6 28 12 8047-8055
spelling	10.1007/s13277-015-4707-1 doi (DE-627)SPR031175317 (SPR)s13277-015-4707-1-e DE-627 ger DE-627 rakwb eng Zhai, Beibei verfasserin aut MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213 Zhang, Xiaofeng aut Sun, Bin aut Cao, Lu aut Zhao, Linlin aut Li, Jun aut Ge, Naijian aut Chen, Lei aut Qian, Haihua aut Yin, Zhengfeng (orcid)0000-0001-6203-9507 aut Enthalten in Tumor biology Amsterdam : IOS Press, 1987 37(2015), 6 vom: 28. Dez., Seite 8047-8055 (DE-627)300897855 (DE-600)1483579-4 1423-0380 nnns volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055 https://dx.doi.org/10.1007/s13277-015-4707-1 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_22 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_63 GBV_ILN_95 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_370 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4338 AR 37 2015 6 28 12 8047-8055
allfields_unstemmed	10.1007/s13277-015-4707-1 doi (DE-627)SPR031175317 (SPR)s13277-015-4707-1-e DE-627 ger DE-627 rakwb eng Zhai, Beibei verfasserin aut MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213 Zhang, Xiaofeng aut Sun, Bin aut Cao, Lu aut Zhao, Linlin aut Li, Jun aut Ge, Naijian aut Chen, Lei aut Qian, Haihua aut Yin, Zhengfeng (orcid)0000-0001-6203-9507 aut Enthalten in Tumor biology Amsterdam : IOS Press, 1987 37(2015), 6 vom: 28. Dez., Seite 8047-8055 (DE-627)300897855 (DE-600)1483579-4 1423-0380 nnns volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055 https://dx.doi.org/10.1007/s13277-015-4707-1 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_22 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_63 GBV_ILN_95 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_370 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4338 AR 37 2015 6 28 12 8047-8055
allfieldsGer	10.1007/s13277-015-4707-1 doi (DE-627)SPR031175317 (SPR)s13277-015-4707-1-e DE-627 ger DE-627 rakwb eng Zhai, Beibei verfasserin aut MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213 Zhang, Xiaofeng aut Sun, Bin aut Cao, Lu aut Zhao, Linlin aut Li, Jun aut Ge, Naijian aut Chen, Lei aut Qian, Haihua aut Yin, Zhengfeng (orcid)0000-0001-6203-9507 aut Enthalten in Tumor biology Amsterdam : IOS Press, 1987 37(2015), 6 vom: 28. Dez., Seite 8047-8055 (DE-627)300897855 (DE-600)1483579-4 1423-0380 nnns volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055 https://dx.doi.org/10.1007/s13277-015-4707-1 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_22 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_63 GBV_ILN_95 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_370 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4338 AR 37 2015 6 28 12 8047-8055
allfieldsSound	10.1007/s13277-015-4707-1 doi (DE-627)SPR031175317 (SPR)s13277-015-4707-1-e DE-627 ger DE-627 rakwb eng Zhai, Beibei verfasserin aut MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213 Zhang, Xiaofeng aut Sun, Bin aut Cao, Lu aut Zhao, Linlin aut Li, Jun aut Ge, Naijian aut Chen, Lei aut Qian, Haihua aut Yin, Zhengfeng (orcid)0000-0001-6203-9507 aut Enthalten in Tumor biology Amsterdam : IOS Press, 1987 37(2015), 6 vom: 28. Dez., Seite 8047-8055 (DE-627)300897855 (DE-600)1483579-4 1423-0380 nnns volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055 https://dx.doi.org/10.1007/s13277-015-4707-1 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_22 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_63 GBV_ILN_95 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_370 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4338 AR 37 2015 6 28 12 8047-8055
language	English
source	Enthalten in Tumor biology 37(2015), 6 vom: 28. Dez., Seite 8047-8055 volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055
sourceStr	Enthalten in Tumor biology 37(2015), 6 vom: 28. Dez., Seite 8047-8055 volume:37 year:2015 number:6 day:28 month:12 pages:8047-8055
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Hepatocellular carcinoma Liver cancer stem cells Sorafenib MK2206
isfreeaccess_bool	false
container_title	Tumor biology
authorswithroles_txt_mv	Zhai, Beibei @@aut@@ Zhang, Xiaofeng @@aut@@ Sun, Bin @@aut@@ Cao, Lu @@aut@@ Zhao, Linlin @@aut@@ Li, Jun @@aut@@ Ge, Naijian @@aut@@ Chen, Lei @@aut@@ Qian, Haihua @@aut@@ Yin, Zhengfeng @@aut@@
publishDateDaySort_date	2015-12-28T00:00:00Z
hierarchy_top_id	300897855
id	SPR031175317
language_de	englisch
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author	Zhai, Beibei
spellingShingle	Zhai, Beibei misc Hepatocellular carcinoma misc Liver cancer stem cells misc Sorafenib misc MK2206 MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK
authorStr	Zhai, Beibei
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topic_title	MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK Hepatocellular carcinoma (dpeaa)DE-He213 Liver cancer stem cells (dpeaa)DE-He213 Sorafenib (dpeaa)DE-He213 MK2206 (dpeaa)DE-He213
topic	misc Hepatocellular carcinoma misc Liver cancer stem cells misc Sorafenib misc MK2206
topic_unstemmed	misc Hepatocellular carcinoma misc Liver cancer stem cells misc Sorafenib misc MK2206
topic_browse	misc Hepatocellular carcinoma misc Liver cancer stem cells misc Sorafenib misc MK2206
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title	MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK
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title_full	MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK
author_sort	Zhai, Beibei
journal	Tumor biology
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author_browse	Zhai, Beibei Zhang, Xiaofeng Sun, Bin Cao, Lu Zhao, Linlin Li, Jun Ge, Naijian Chen, Lei Qian, Haihua Yin, Zhengfeng
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title_sort	mk2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pakt and upregulation of perk
title_auth	MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK
abstract	Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. © International Society of Oncology and BioMarkers (ISOBM) 2015
abstractGer	Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. © International Society of Oncology and BioMarkers (ISOBM) 2015
abstract_unstemmed	Abstract Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib. © International Society of Oncology and BioMarkers (ISOBM) 2015
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title_short	MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK
url	https://dx.doi.org/10.1007/s13277-015-4707-1
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author2	Zhang, Xiaofeng Sun, Bin Cao, Lu Zhao, Linlin Li, Jun Ge, Naijian Chen, Lei Qian, Haihua Yin, Zhengfeng
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up_date	2024-07-03T22:25:24.594Z
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MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK

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