EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity

Nicholas J. Donato, Margot Perez, Hyunseok Kang, Zahid H. Siddik, Yi He Ling, Roman Perez-Soler

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 ~80 ng/ml in cDDP sensitive (PT-S) to ~2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (~30- fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME- 180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.

Original languageEnglish (US)
Pages (from-to)193-202
Number of pages10
JournalClinical Cancer Research
Volume6
Issue number1
StatePublished - Jan 2000
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Cisplatin
Carcinoma
Cell Cycle
Pharmaceutical Preparations
Signal Transduction
Camptothecin
DNA Adducts
Drug Resistance
DNA Repair
Inhibitory Concentration 50
Neoplasms
Cell Death
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity. / Donato, Nicholas J.; Perez, Margot; Kang, Hyunseok; Siddik, Zahid H.; Ling, Yi He; Perez-Soler, Roman.

In: Clinical Cancer Research, Vol. 6, No. 1, 01.2000, p. 193-202.

Research output: Contribution to journalArticle

Donato, Nicholas J. ; Perez, Margot ; Kang, Hyunseok ; Siddik, Zahid H. ; Ling, Yi He ; Perez-Soler, Roman. / EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 1. pp. 193-202.
@article{f8565f53f4a84c4791c8edbee9eac1ce,
title = "EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity",
abstract = "Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 ~80 ng/ml in cDDP sensitive (PT-S) to ~2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (~30- fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME- 180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.",
author = "Donato, {Nicholas J.} and Margot Perez and Hyunseok Kang and Siddik, {Zahid H.} and Ling, {Yi He} and Roman Perez-Soler",
year = "2000",
month = "1",
language = "English (US)",
volume = "6",
pages = "193--202",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity

AU - Donato, Nicholas J.

AU - Perez, Margot

AU - Kang, Hyunseok

AU - Siddik, Zahid H.

AU - Ling, Yi He

AU - Perez-Soler, Roman

PY - 2000/1

Y1 - 2000/1

N2 - Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 ~80 ng/ml in cDDP sensitive (PT-S) to ~2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (~30- fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME- 180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.

AB - Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 ~80 ng/ml in cDDP sensitive (PT-S) to ~2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (~30- fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME- 180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.

UR - http://www.scopus.com/inward/record.url?scp=0033985682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033985682&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 193

EP - 202

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -