KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer

Yohei Sekino,Naoya Sakamoto,Kazuhiro Sentani,Wataru Yasui,Yuki Koike,Yoshinori Shigematsu,Masaki Shiota,Jun Teishima,Akio Matsubara,Naohide Oue

doi:10.3390/jcm8020225

Yohei Sekino, Naoya Sakamoto + Show 8 more

Open Access

https://doi.org/10.3390/jcm8020225

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Abstract

Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance.

Highlights

Prostate cancer (PCa) is the most prevalent cancer 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 a marker of apoptosis in the parental and DTX-resistant cell lines
Western blotting showed that the expression of c-PARP and c-caspase-3 was induced by DTX treatment in the parental DU145 and C4-2 cells

Summary

Introduction

Prostate cancer (PCa) is the most prevalent cancer among men and the second leading cause of cancer-related death in developed countries [1]. Androgen deprivation therapy is initially effective for advanced PCa. Androgen deprivation therapy is initially effective for advanced PCa Most of these patients eventually progress to castration-resistant PCa (CRPC), which is a life-threatening disease [2,3]. Docetaxel (DTX) is the standard chemotherapy for CRPC [4]. Most patients who are treated with DTX become refractory. Clarifying new molecular mechanisms underlying DTX resistance is necessary to overcome DTX resistance in CRPC

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