Low inducible expression of p21Cip1 confers resistance to paclitaxel in BRAF mutant melanoma cells with acquired resistance to BRAF inhibitor
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The therapeutic efficacy of oncogenic BRAF inhibitor is limited by the onset of acquired resistance. In this study, we investigated the potential therapeutic effects of the mitotic inhibitor paclitaxel on three melanoma cell lines with differing sensitivity to the BRAF inhibitor. Of the two BRAF inhibitor-resistant cell lines, A375P/Mdr cells harboring the BRAF V600E mutant were resistant and the wild-type BRAF SK-MEL-2 cells were sensitive to paclitaxel. In particular, paclitaxel caused the growth inhibition of SK-MEL-2 cells to a much greater extent than it caused growth inhibition of A375P cells. Paclitaxel exhibited no significant effect on the phosphorylation of MEK-ERK in any cell lines tested, regardless of both the BRAF mutation and the drug resistance, implying that paclitaxel activity is independent of MEK-ERK inhibition. In A375P cells, paclitaxel treatment resulted in a marked emergence of apoptotic cells after mitotic arrest, concomitant with a remarkable induction of p21Cip1. However, paclitaxel only moderately increased the levels of p21Cip1 in A375P/Mdr cells, which exhibited a strong resistance to paclitaxel. The p21Cip1 overexpression partially conferred paclitaxel sensitivity to A375P/Mdr cells. Interestingly, we found an extremely low background expression level of p21Cip1 in SK-MEL-2 cells lacking normal p53 function, which caused much greater G2/M arrest than that seen in A375P cells. Taken together, these results suggest that paclitaxel may be an effective anticancer agent through regulating the expression of p21Cip1 for the treatment of BRAF mutant melanoma cells resistant to BRAF inhibitors.
KeywordsPaclitaxel BRAF inhibitor-resistance Melanoma Mitotic arrest p21Cip1 Apoptosis
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013R1A1A2A10058897).
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