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Article
Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53
Gynecologic oncology
  • Xiangbing Meng, University of Iowa
  • Laura L. Laidler
  • Elizabeth A. Kosmacek, University of Iowa
  • Shujie Yang, University of Iowa
  • Zhi Xiong, University of Iowa
  • Danlin Zhu, University of Iowa
  • Xinjun Wang, University of Iowa
  • Donghai Dai, University of Iowa
  • Yuping Zhang, University of Iowa
  • Xiaofang Wang, University of Iowa
  • Pavia Brachova, University of Iowa
  • Lina Albitar
  • Dawei Liu, University of Iowa
  • Florenza Ianzini, University of Iowa
  • Michael A. Mackey, University of Iowa
  • Kimberly K. Leslie, University of Iowa
Document Type
Article
Peer Reviewed
1
Publication Date
3-1-2013
NLM Title Abbreviation
Gynecol Oncol
PubMed ID
23146687
DOI of Published Version
10.1016/j.ygyno.2012.11.004
Abstract
OBJECTIVE: Endometrial tumors with non-functional p53, such as serous uterine endometrial carcinomas, are aggressive malignancies with a poor outcome, yet they have an Achilles' heel: due to loss of p53 function, these tumors may be sensitive to treatments which abrogate the G2/M checkpoint. Our objective was to exploit this weakness to induce mitotic cell death using two strategies: (1) EGFR inhibitor gefitinib combined with paclitaxel to arrest cells at mitosis, or (2) BI2536, an inhibitor of polo-like kinase 1 (PLK1), to block PLK1 activity. METHODS: We examined the impact of combining gefitinib and paclitaxel or PLK1 inhibitor on expression of G2/M checkpoint controllers, cell viability, and cell cycle progression in endometrial cancer cells with mutant p53. RESULTS: In cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis. Live cell imaging demonstrated irreversible mitotic arrest and eventual cell death. Combinatorial therapy with paclitaxel and gefitinib was highly synergistic and resulted in a 10-fold reduction in the IC50 for paclitaxel, from 14nM as a single agent to 1.3nM in the presence of gefitinib. However, BI2536 alone at low concentrations (5nM) was the most effective treatment and resulted in massive mitotic cell death. In a xenograft mouse model with p53-deficient cells, low dose BI2536 significantly inhibited tumor growth. CONCLUSIONS: These findings reveal induction of mitotic cell death as a therapeutic strategy for endometrial tumors lacking functional p53.
Published Article/Book Citation

Gynecologic oncology, 128:3 (2013) pp.461-469.

Citation Information
Xiangbing Meng, Laura L. Laidler, Elizabeth A. Kosmacek, Shujie Yang, et al.. "Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53" Gynecologic oncology Vol. 128 Iss. 3 (2013) p. 461 - 469 ISSN: 1095-6859
Available at: http://works.bepress.com/donghai_dai/12/