Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines.

Kazuaki Machioka,Jian Zhang,Atsushi Mizokami,Yoshifumi Kadono,Renato Naito,Kouji Izumi,Tomoyuki Makino,Suguru Kadomoto,Hiroaki Iwamoto,Ariunbold Natsagdorj,Evan T Keller

doi:10.18632/oncotarget.24609

Kazuaki Machioka, Jian Zhang + Show 9 more

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https://doi.org/10.18632/oncotarget.24609

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Once castration-resistant prostate cancer (CRPC) become resistant for cabazitaxel treatment, the patients are obliged to best supportive care. Therefore, the elucidation of the mechanism of the cabazitaxel-resistance and the conquest are important themes to improve the prognosis of the patients. Then we tried to establish cabazitaxel-resistant CRPC cell lines and characterized them. We established two cabazitaxel-resistant cell lines, PC-3-TxR/CxR and DU145-TxR/CxR from PC-3-TxR and DU145-TxR cell lines previously we established. PC-3-TxR/CxR and DU145-TxR/CxR cells became resistant for cabazitaxel by 11.8-fold and 4.4-fold, respectively. The TxR/CxR cells showed cabazitaxel-resistant using SCID mice in vivo. Although expression of multi-drug resistance gene 1 (MDR1) was up-regulated in DU145-TxR compared with DU145 cells, it was not up-regulated in DU145-TxR/CxR cells any more. In contrast, expression of MDR1 gene was up-regulated in PC-3-TxR compared with PC-3 cells and it was further up-regulated in PC-3-TxR/CxR compared with PC-3-TxR cells. Comparison of cDNA microarray between PC-3-TxR and PC-3-TxR/CxR cells or between DU145-TxR and DU145-TxR/CxR cells revealed that many genes were up-regulated or down-regulated. Finally, knockdown of MDR1 recovered the sensitivity to cabazitaxel not only in PC-3-TxR/CxR cells but also DU145-TxR/CxR cells. Together, regulation of MDR1 gene is important for conquest of the cabazitaxel-resistance.

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Prostate cancer (PCa) is the most common malignancy and the second most frequent cause of cancer related death of men in the United States in 2017
We speculated that DU145-TxR cells demonstrated greater cabazitaxel-resistance than PC-3-TxR cells as we previously demonstrated that DU145-TxR cells had higher P-gp expression than PC-3-TxR cells [14]
The observation that cabazitaxel is effective in castration-resistant prostate cancer (CRPC) patients that have developed docetaxel resistance suggests that mechanisms, other than those that account for docetaxel resistance, contribute to the development of cabazitaxel resistance after failure of docetaxel treatment

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Introduction

Prostate cancer (PCa) is the most common malignancy and the second most frequent cause of cancer related death of men in the United States in 2017. Androgen deprivation treatment is very effective at inducing response for advanced or metastatic PCa [2, 3]. More than half of those cases become resistant to androgen deprivation treatment after several years [4] in what is termed castration resistant prostate cancer (CRPC). In 2012, the food and drug administration (FDA) in the United States approved the use of abiraterone and enzalutamide as effective treatments for CRPC [5, 6]. They eventually fail and chemotherapeutics, primarily taxanes, are initiated. Docetaxel resistance can develop through numerous mechanisms, including androgen receptor (AR)

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