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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2013.1
- 수록면
- 114 - 120 (7page)
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Most patients with mutant B-Raf melanomas respond to inhibitors of oncogenic B-Raf but resistance eventually emerges. To better understand the mechanisms that determine the long-term responses of mutant B-Raf melanoma cells to B-Raf inhibitor, we used chronic selection to establish B-Raf (V600E) melanoma clones with acquired resistance to the new oncogenic B-Raf inhibitor UI-152. Whereas the parental A375P cells were highly sensitive to UI-152 ($IC_{50}$ < $0.5{\mu}M$), the resistant sub-line (A375P/Mdr) displayed strong resistance to UI-152 ($IC_{50}$ < $20{\mu}M$). Immunofluorescence analysis indicated the absence of an increase in the levels of P-glycoprotein multidrug resistance (MDR) transporter in A375P/Mdr cells, suggesting that resistance was not attributable to P-glycoprotein overexpression. In UI-152-sensitive A375P cells, the anti-proliferative activity of UI-152 appeared to be due to cell-cycle arrest at $G_0/G_1$ with the induction of apoptosis. However, we found that A375P/Mdr cells were resistant to the apoptosis induced by UI-152. Interestingly, UI-152 preferentially induced autophagy in A375P/Mdr cells but not in A375P cells, as determined by GFP-LC3 puncta/cell counts. Further, autophagy inhibition with 3-methyladenine (3-MA) partially augmented growth inhibition of A375P/Mdr cells by UI-152, which implies that a high level of autophagy may protect UI-152-treated cells from undergoing growth inhibition. Together, our data implicate high rates of autophagy as a key mechanism of acquired resistance to the oncogenic B-Raf inhibitor, in support of clinical studies in which combination therapy with autophagy targeted drugs is being designed to overcome resistance.
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참고문헌 (34)
참고문헌 신청
Ahn, J. -H. / 2012 / The role of autophagy in cytotoxicity induced by new oncogenic B-Raf inhibitor UI-152 in v-Ha-ras transformed fibroblasts / Biochem. Biophys. Res. Commun 417:857~863
Jun-Ho Ahn / 2010 / Spry2 does not directly modulate Raf-1 kinase activity in v-Ha-ras-transformed NIH 3T3 fibroblasts / BMB Reports 43(3):205~211
Ahn, J.-H. / 2011 / Suppression of autophagy sensitizes multidrug resistant cells towards Src tyrosine kinase specific inhibitor PP2 / Cancer Lett 310:188~197
Blagosklonny, M. V. / 2007 / Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events / Cell Cycle 6:70~74
Cagnol, S. / 2010 / ERK and cell death: mechanisms of ERK-induced cell death - apoptosis, autophagy and senescence / FEBS J 277:2~21
Jun-Ho Ahn / 2010 / Spry2 does not directly modulate Raf-1 kinase activity in v-Ha-ras-transformed NIH 3T3 fibroblasts / BMB Reports 43(3):205~211
Ahn, J.-H. / 2011 / Suppression of autophagy sensitizes multidrug resistant cells towards Src tyrosine kinase specific inhibitor PP2 / Cancer Lett 310:188~197
Blagosklonny, M. V. / 2007 / Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events / Cell Cycle 6:70~74
Cagnol, S. / 2010 / ERK and cell death: mechanisms of ERK-induced cell death - apoptosis, autophagy and senescence / FEBS J 277:2~21
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