Abstract
Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.
Highlights
Prostate cancer (PCa) is the most common solid malignancy among men and the second leading cause of cancer-related death in developed countries [1]
We compared the expression of cleaved PARP (c-PARP), which was used as an apoptosis marker, in parental and CBZ-resistant cells in LNCaP and 22Rv-1 cells
The IC50 values of CBZ-resistant cells were significantly higher than those of parental cells in LNCaP and 22Rv-1 cells (Figure 1D). These results indicate that cross-resistance between DTX and CBZ exists in PCa
Summary
Prostate cancer (PCa) is the most common solid malignancy among men and the second leading cause of cancer-related death in developed countries [1]. Prostate-specific antigen testing to screen for early-stage PCa is widely used, approximately 30% of patients are newly diagnosed as having locally advanced or metastatic disease [2]. Androgen deprivation therapy is initially effective in treating advanced PCa; most of these patients progress to castration-resistant PCa (CRPC) [3]. Most patients treated with DTX and CBZ become refractory due to the development of resistance to these therapies. Several recent reports have shown cross-resistance between DTX and CBZ [6,7].
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