Low inducible expression of p21Cip1 confers resistance to paclitaxel in BRAF mutant melanoma cells with acquired resistance to BRAF inhibitor

Abstract

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 p21(Cip1). However, paclitaxel only moderately increased the levels of p21(Cip1) in A375P/Mdr cells, which exhibited a strong resistance to paclitaxel. The p21(Cip1) overexpression partially conferred paclitaxel sensitivity to A375P/Mdr cells. Interestingly, we found an extremely low background expression level of p21(Cip1) 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 p21(Cip1) for the treatment of BRAF mutant melanoma cells resistant to BRAF inhibitors.

Upregulation of MicroRNA-1246 Is Associated with BRAF Inhibitor Resistance in Melanoma Cells with Mutant BRAF

“…We detected a remarkable decrease of p21 Cip1 in A375P/Mdr cells after PLX4720 treatment. We previously found a relatively high background expression level of p21 Cip1 in A375P/Mdr cells compared to A375P cells [ 15 ]. Conversely, PLX4720 treatment only moderately increased the levels of p27 Kip1 in A375P/Mdr cells.…”

Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy

“…p21, is required to maintain the G2 arrest after DNA damage [ 46 ], the level of p21 expression has been known to play an important role in determining sensitivity of tumor cells to PTX [ 47 ], and a remarkable induction of p21 in A375P cells after treatment of PTX and apoptosis induction after mitotic arrest with PTX. However, PTX lightly increased the levels of p21 in A375P/Mdr cells, which exhibited strong resistance to PTX [ 48 ]. p16, mainly inhibits CDK4 activity, the loss of p16 expression reduced the response of breast cancer cells to PTX by conferring cancer stem cell properties and the tumorsphere formation was not significantly enhanced [ 49 ], those results indicated that CKIs affect PTX efficacy mainly through the cell cycle regulation.…”

Tumor suppressor genes and their interactions and neo-adjuvant therapy in paclitaxel resistance in cancer

“…The degree of p21 expression has been established to play a significant role in determining tumour cell susceptibility to PTX [36] , and a notable elevation of p21 in A375P cells following PTX treatment and apoptotic induction after mitotic arrest with PTX. However, PTX only slightly boosted the levels of p21 in A375P/Mdr cells, which were resistant to PTX [37] .…”