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

doi:10.1016/j.abb.2007.03.040

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 journal › Article › peer-review

14 Scopus citations

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/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.

Original language	English (US)
Pages (from-to)	19-27
Number of pages	9
Journal	Archives of Biochemistry and Biophysics
Volume	464
Issue number	1
DOIs	https://doi.org/10.1016/j.abb.2007.03.040
State	Published - Aug 1 2007
Externally published	Yes

Keywords

Calcium
Prostate cancer
Resistance
SERCA
Thapsigargin

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology

Access to Document

10.1016/j.abb.2007.03.040

Cite this

@article{b43d3d5d87b040b3b0ce4db16e82dfc3,

title = "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 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.",

keywords = "Calcium, Prostate cancer, Resistance, SERCA, Thapsigargin",

author = "Lee, {Dong I.} and Carlota Sumbilla and Myounghee Lee and Chidambaram Natesavelalar and Klein, {Michael G.} and Ross, {Douglas D.} and Giuseppe Inesi and Arif Hussain",

note = "Funding Information: The work was supported, in part, by grant from a Merit Review Award in the Medical Research Service, Department of Veterans Affairs (D.R, A.H). Copyright: Copyright 2009 Elsevier B.V., All rights reserved.",

year = "2007",

month = aug,

day = "1",

doi = "10.1016/j.abb.2007.03.040",

language = "English (US)",

volume = "464",

pages = "19--27",

journal = "Archives of Biochemistry and Biophysics",

issn = "0003-9861",

publisher = "Academic Press Inc.",

number = "1",

}

TY - JOUR

T1 - Mechanisms of resistance and adaptation to thapsigargin in androgen-independent prostate cancer PC3 and DU145 cells

AU - Lee, Dong I.

AU - Sumbilla, Carlota

AU - Lee, Myounghee

AU - Natesavelalar, Chidambaram

AU - Klein, Michael G.

AU - Ross, Douglas D.

AU - Inesi, Giuseppe

AU - Hussain, Arif

N1 - Funding Information: The work was supported, in part, by grant from a Merit Review Award in the Medical Research Service, Department of Veterans Affairs (D.R, A.H). Copyright: Copyright 2009 Elsevier B.V., All rights reserved.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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.

AB - 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.

KW - Calcium

KW - Prostate cancer

KW - Resistance

KW - SERCA

KW - Thapsigargin

UR - http://www.scopus.com/inward/record.url?scp=34447646551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447646551&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2007.03.040

DO - 10.1016/j.abb.2007.03.040

M3 - Article

C2 - 17475205

AN - SCOPUS:34447646551

SN - 0003-9861

VL - 464

SP - 19

EP - 27

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this