Mechanisms of resistance and adaptation to thapsigargin in androgen-independent prostate cancer PC3 and DU145 cells

Dong I. Lee, Carlota Sumbilla, Myounghee Lee, Chidambaram Natesavelalar, Michael G. Klein, Douglas D. Ross, Giuseppe Inesi, Arif Hussain

Research output: Contribution to journalArticlepeer-review

Abstract

Cells with increasing resistance to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor thapsigargin (TG), ranging from 60-fold (PC3/TG10 cells) to 1350-fold (PC3/TG2000 cells), were derived from PC3 cells. SERCA2 is overexpressed in all PC3/TG cells but retains sensitivity to TG. siRNA-mediated downregulation of SERCA completely or partially reverses TG resistance in PC3/TG10 or PC3/TG2000 cells, respectively; thus SERCA overexpression mediates resistance in PC3/TG10 cells but is not the only resistance mechanism in PC3/TG2000 cells. By contrast, SERCA is not overexpressed in TG-resistant DU145/TG cells derived from DU145 cells. DU145/TG cells retain resistance while in PC3/TG cells resistance decreases upon removal of TG selection. The transport proteins PGP/BCRP/MRP1 and anti-apoptotic proteins Bcl2/BclXL are not involved in mediating resistance in either cell line. PARP and caspase 3 cleavage in response to other drugs demonstrate that the apoptotic pathways tested remain intact in these cells. Further, no cross-resistance occurs to other drugs. Thus, novel TG-specific resistance mechanisms are recruited by these cancer cells.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume464
Issue number1
DOIs
StatePublished - Aug 1 2007
Externally publishedYes

Keywords

  • Calcium
  • Prostate cancer
  • Resistance
  • SERCA
  • Thapsigargin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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