Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells

Steven L. Warner, Bret J. Stephens, Stanley Nwokenkwo, Galen Hostetter, Anastasia Sugeng, Manuel Hidalgo, Jeffery M. Trent, Haiyong Han, Daniel D. Von Hoff

Research output: Contribution to journalArticle

Abstract

Purpose: The targeting protein for Xklp2 (TPX2) has recently gainedattention as a putative oncogene possibly amplifiedin several human malignancies, including pancreatic adenocarcinoma. In this work, we sought to evaluate the copy number and expression of TPX2 in pancreatic cancer cell lines andtumor tissues andto further explore the potential of TPX2 as a therapeutic target. Experimental Design: The DNA copy number andexpression of the TPX2 gene were surveyedi n pancreatic cancer cell lines andtumo r tissues andcom paredwi th those of immortalizednormal pancreatic ductal cells andnormal pancreatic tissues. The cellular effects of TPX2 knockdown using small interfering RNA oligonucleotides in pancreatic cancer cells, such as growth in tissue culture, in soft agar, andi n nude mice; apoptosis; andsensitivity to paclitaxel, were also investigated using various assays. Results: Low-copy-number TPX2 amplification was foundin pancreatic cancer cell lines andl ow-passage pancreatic cancer tumor xenografts. TPX2 expression was upregulatedin pancreatic cancer cell lines at both the mRNA and protein levels relative to the immortalizedpancr eatic ductal epithelial cell line HPDE6. Immunohistochemical staining of a tissue microarray showedthat TPX2 expression was higher in pancreatic tumors comparedwith their normal counterparts. Treatment with TPX2 targeting small interfering RNAs effectively reduced pancreatic cancer cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar and in nude mice. Knockdown of TPX2 also sensitizedpancreatic cancer cells to paclitaxel treatment. Conclusions: Our results suggest that TPX2 might be an attractive target for pancreatic cancer therapy.

Original languageEnglish (US)
Pages (from-to)6519-6528
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number21
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Warner, S. L., Stephens, B. J., Nwokenkwo, S., Hostetter, G., Sugeng, A., Hidalgo, M., Trent, J. M., Han, H., & Von Hoff, D. D. (2009). Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells. Clinical Cancer Research, 15(21), 6519-6528. https://doi.org/10.1158/1078-0432.CCR-09-0077