Functional p53 determines docetaxel sensitivity in prostate cancer cells

Abstract

BACKGROUND Docetaxel is the first line treatment for castration resistant prostate cancer (CRPC). However, docetaxel resistance rapidly develops. Identifying the critical mechanisms giving rise to docetaxel resistance is the major challenge in advanced prostate cancer. METHODS The effects of docetaxel on human DU145, PC3, LNCaP, and C4-2 prostate cancer cells were examined in cell culture, and p53 expression were analyzed by Western blot analysis. The potential role of p53 in docetaxel sensitivity in prostate cancer cells was tested by either p53 silencing using shRNA or p53 overexpression by introducing wild-type p53. RESULTS We found that DU145 (mutant p53) and PC3 (p53 null) cells were less sensitive than LNCaP and C4-2 cells expressing functional p53 in response to docetaxel. Docetaxel treatment induces considerably higher apoptosis in LNCaP and C4-2 cells than in DU145 and PC3 cells in a dose dependent manner. Docetaxel increases the levels of ser15 phosphorylation of p53 in a dose dependent manner in both LNCaP and C4-2 cells, while has no effect on the levels of ser15 phosphorylation of p53 in DU145 cells. These results suggest that p53 phosphorylation is associated with docetaxel sensitivity in prostate cancer cells. To further confirm whether p53 activation can induce cell sensitivity to docetaxel treatment, we used p53 shRNA to knock down p53 expression in C4-2 cells and determined the cells response to docetaxel treatment. Knockdown of p53 significantly down regulated p53 phosphorylation and blocked docetaxel induced apoptotic cell death compared to the vector control. To further confirm this observation, we established a stable knock out p53 in C4-2 cells. Down regulation of p53 in the stable p53 knock out C4-2 cells significantly inhibited docetaxel induced apoptotic cell death. We also used wild-type (WT) p53 to over express p53 in DU145 cells, and found that expression of WT-p53 in DU145 cells increased their sensitivity to docetaxel. CONCLUSIONS These results demonstrate that docetaxel induces p53 phosphorylation and that p53 status is a crucial determinant of docetaxel sensitivity in prostate cancer cells.

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

“…Furthermore, such cells with restored AR activity can also lower drug resistance because androgen-dependent cells are also more sensitive to chemotherapy than are androgen-independent cells (70). A corollary to the bipolar ADT treatment (67) that stems from our model is that higher levels of PAGE4 would predict a better prognosis.…”

Targeted nanomedicine for prostate cancer therapy: docetaxel and curcumin co-encapsulated lipid–polymer hybrid nanoparticles for the enhanced anti-tumor activityin vitroandin vivo

“…On one hand, the molecular mechanism of CUR induced cytotoxicity in prostate cancer cells possess multiple targets including inhibition of cyclin D1 and upregulation of p53, leading to cell cycle arrest at G1/S phase; downregulation of NF-kB and P-glycoprotein; and inhibition of androgen receptor activated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 expression involved in HRPC proliferation, etc. On the other hand, aberrant activation of multiple cellular signaling pathways such as p53, NF-kB, PI3K-Akt, and IL-6/ STAT3 is associated with docetaxel resistance as well (Liu et al, 2013;Zhu et al, 2015). Therefore, CUR could decrease hormone refractory (HR) PC aggressive proliferation and potentiate activity of DTX therapy, and prevent PC cell resistance to DTX.…”

Effect of p53 gene polymorphism on functions of prostate cancer cells

“…The p53 gene is a negative regulatory factor in the cell growth cycle and is associated with important biological functions such as cell cycle regulation, DNA repair, cell differentiation, and cell apoptosis, among others (Liu et al, 2013). The p53 gene and its products are divided into wild type and mutant type.…”