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

Abstract

Cells with increasing resistance to the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin (TG), ranging from 60-fold (PC3/TG(10) cells) to 1350-fold (PC3/TG(2000) 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/TG(10) or PC3/TG(2000) cells, respectively; thus SERCA overexpression mediates resistance in PC3/TG(10) cells but is not the only resistance mechanism in PC3/TG(2000) 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/Bcl(XL) 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.

• Authors: Dong I Lee, Carlota Sumbilla, Myounghee Lee, Chidambaram Natesavelalar, Michael G Klein, Douglas D Ross, Giuseppe Inesi, Arif Hussain
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 464 Issue 1 Pg. 19-27 (Aug 01 2007) ISSN: 0003-9861 [Print] United States
• PMID: 17475205 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgens
• Enzyme Inhibitors
• RNA, Small Interfering
• Thapsigargin
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• ATP2A2 protein, human
• Calcium

Topics

• Androgens (metabolism)
• Apoptosis
• Calcium (metabolism)
• Cell Line, Tumor
• Cytosol (metabolism)
• Drug Resistance
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Gene Silencing
• Humans
• Male
• Prostatic Neoplasms (metabolism)
• RNA, Small Interfering (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Thapsigargin (chemistry, pharmacology)