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Overexpression of Glycogen Synthase Kinase-3 in Ovarian Carcinoma Cells With Acquired Paclitaxel Resistance
  1. Yunfeng Fu, PhD*,
  2. Dongxiao Hu, MD*,
  3. Jian Qiu, MD*,
  4. Xing Xie, MD*,,
  5. Feng Ye, PhD and
  6. Wei-Guo Lu, PhD*,
  1. *Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; and
  2. Women's Reproductive and Health Laboratory of Zhejiang Province, Hangzhou, China.
  1. Address correspondence and reprint requests to Wei-Guo Lu, PhD, Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, 2 Xueshi Rd, Hangzhou, 310006, China. E-mail: lbwg{at}zju.edu.cn.

Abstract

Introduction Acquired resistance to paclitaxel, including regimens, is one of the most significant reasons for treatment failure and death in patients with ovarian cancer, but the causes of this resistance remain unclear. However, cell cycle regulation is a key mechanism by which most chemotherapeutic agents exert their cytotoxic effects.

Methods We created a paclitaxel-resistant ovarian carcinoma cell line from SKOV3 cell line, and the difference of cell cycle distribution was analyzed using flow cytometry. Analysis of human cell cycle pathway complementary DNA array was performed to identify candidate genes associated with paclitaxel resistance. Gene expression changes were validated at the messenger RNA and protein levels by real-time reverse transcriptase polymerase chain reaction and Western analysis, respectively.

Results The ratio of Gap0/Gap1 phase in SKOV3-TR30 was significantly lower than that in SKOV3 (54.8% ± 6.3% vs 72.7% ± 7.6%, P = 0.035), and the ratio of G2/M phase in SKOV3-TR30 was significantly higher than that in SKOV3 (24.9% ± 6.0% vs 10.2% ± 3.5%, P = 0.021). Complementary DNA microarray analysis demonstrated enhanced glycogen synthase kinase-3α (GSK-3α) expression in paclitaxel-resistant ovarian carcinoma cells. Real-time reverse transcriptase polymerase chain reaction analysis revealed that the paclitaxel-resistant subline exhibited a 7.0 ± 1.8-fold increase in GSK-3α messenger RNA expression. There was a 3.34 ± 0.47-fold increase of total GSK-3 protein (GSK-3α/β) in SKOV3-TR30 cells validated by Western analysis.

Conclusions This study demonstrates that enhanced expression of GSK-3 is associated with acquired resistance to paclitaxel in ovarian carcinoma cells. Glycogen synthase kinase-3 overexpression may probably be a significant contributor to chemoresistance.

  • Ovarian carcinoma
  • Paclitaxel
  • Drug resistance
  • Glycogen synthase kinase-3
  • Gene expression

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Footnotes

  • This work was supported by the National Natural Science Foundation of China (30901591) and the Foundation of Education of Zhejiang Province (Y200909325).

  • The authors have no competing interests.

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