TY - JOUR
T1 - Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer
AU - Babasaki, Takashi
AU - Sentani, Kazuhiro
AU - Sekino, Yohei
AU - Kobayashi, Go
AU - Thang Pham, Quoc
AU - Katsuya, Narutaka
AU - Akabane, Shintaro
AU - Taniyama, Daiki
AU - Hayashi, Tetsutaro
AU - Shiota, Masaki
AU - Oue, Naohide
AU - Teishima, Jun
AU - Matsubara, Akio
AU - Yasui, Wataru
N1 - Funding Information:
This work was supported by Grants‐in‐Aid for Scientific Research (19K07434) from the Japan Society for the Promotion of Science. The Takeda Science Foundation also supported this work.
Publisher Copyright:
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2021/8
Y1 - 2021/8
N2 - Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.
AB - Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.
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U2 - 10.1002/cam4.4113
DO - 10.1002/cam4.4113
M3 - Article
C2 - 34240817
AN - SCOPUS:85109410567
VL - 10
SP - 5574
EP - 5588
JO - Cancer Medicine
JF - Cancer Medicine
SN - 2045-7634
IS - 16
ER -