Thapsigargin resistance in human prostate cancer cells

John P. O'Neill, Chidambaram Natesa Velalar, Dong Ik Lee, Bin Zhang, Takeo Nakanishi, Yao Tang, Florin Selaru, Douglas Ross, Stephen J. Meltzer, Arif Hussain

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Thapsigargin (TG) is a potent inhibitor of sarcoplasmic/ endoplasmic reticulum Ca2+ ATPases (SERCAs). TG-based prodrugs are being developed for the treatment of prostate cancer (PC). To develop optimal TG-based therapeutics it is important to understand the mechanisms of resistance to TG that may potentially occur in cancer cells. METHODS. DU145/TG and PC3/TG cells were derived from human PC DU145 and PC3 cells, respectively, by incremental exposure to TG. Growth assays, Western blot analyses, cDNA microarrays, semiquantitative and real-time polymerase chain reaction (PCR), Northern blot analyses, and immunohistochemistry were used to study these cells. RESULTS. DU145/TG cells are 1100-fold and PC3/TG cells are 1350-fold resistant to TG. Although expression of both SERCA and p-glycoprotein can mediate TG resistance in hamster cells, neither is modulated in DU145/TG cells. In contrast, in PC3/TG cells, SERCA, and not p-glycoprotein, is significantly overexpressed but cannot by itself account for the 1350-fold resistance to TG in these cells. Several genes not previously identified to be altered by TG selection are modulated in DU145/TG and PC3/TG cells. Furthermore, the spectrum of genes modulated in DU145/TG cells are distinct from that in PC3/TG cells, even though both cells are of prostate origin and share the same TG-resistant phenotype. CONCLUSIONS. PC cells can adapt to SERCA inhibition by TG. However, they demonstrate cell type-specific plasticity with respect to gene expression upon TG selection. Further, previously not described mechanisms of resistance appear to be recruited in the TG-resistant PC cells, which provide a novel model to study mechanisms of resistance and adaptation in PC on TG-mediated dysregulation of Ca2+ homeostasis.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalCancer
Volume107
Issue number3
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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Keywords

  • Calcium
  • Drug resistance
  • Microarray
  • Prostate cancer
  • Thapsigargin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

O'Neill, J. P., Velalar, C. N., Lee, D. I., Zhang, B., Nakanishi, T., Tang, Y., Selaru, F., Ross, D., Meltzer, S. J., & Hussain, A. (2006). Thapsigargin resistance in human prostate cancer cells. Cancer, 107(3), 649-659. https://doi.org/10.1002/cncr.22027