Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT: Correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model

Zhihu Ding, Adam G. Green, Xiaolong Yang, Garry Chernenko, Shou-Ching Tang, Alan Pater

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.

Original languageEnglish (US)
Pages (from-to)185-191
Number of pages7
JournalExperimental Cell Research
Volume272
Issue number2
DOIs
StatePublished - Jan 1 2002

Fingerprint

Telomerase
Multiple Drug Resistance
Tretinoin
Carcinogenesis
Down-Regulation
RNA-Directed DNA Polymerase
Growth
Messenger RNA
Ribonucleoproteins
In Vitro Techniques
Proteins
Cell Line

Keywords

  • All-trans-retinoic acid
  • Cell growth rate
  • Cervical cells
  • Immortalization
  • Telomerase
  • Transformation/multidrug resistance
  • hTERT

ASJC Scopus subject areas

  • Cell Biology

Cite this

Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT : Correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model. / Ding, Zhihu; Green, Adam G.; Yang, Xiaolong; Chernenko, Garry; Tang, Shou-Ching; Pater, Alan.

In: Experimental Cell Research, Vol. 272, No. 2, 01.01.2002, p. 185-191.

Research output: Contribution to journalArticle

@article{ef1be10da9874cc0be5045a2e4d09d64,
title = "Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT: Correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model",
abstract = "Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.",
keywords = "All-trans-retinoic acid, Cell growth rate, Cervical cells, Immortalization, Telomerase, Transformation/multidrug resistance, hTERT",
author = "Zhihu Ding and Green, {Adam G.} and Xiaolong Yang and Garry Chernenko and Shou-Ching Tang and Alan Pater",
year = "2002",
month = "1",
day = "1",
doi = "10.1006/excr.2001.5412",
language = "English (US)",
volume = "272",
pages = "185--191",
journal = "Experimental Cell Research",
issn = "0014-4827",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT

T2 - Correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model

AU - Ding, Zhihu

AU - Green, Adam G.

AU - Yang, Xiaolong

AU - Chernenko, Garry

AU - Tang, Shou-Ching

AU - Pater, Alan

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.

AB - Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.

KW - All-trans-retinoic acid

KW - Cell growth rate

KW - Cervical cells

KW - Immortalization

KW - Telomerase

KW - Transformation/multidrug resistance

KW - hTERT

UR - http://www.scopus.com/inward/record.url?scp=0036060531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036060531&partnerID=8YFLogxK

U2 - 10.1006/excr.2001.5412

DO - 10.1006/excr.2001.5412

M3 - Article

C2 - 11777343

AN - SCOPUS:0036060531

VL - 272

SP - 185

EP - 191

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

IS - 2

ER -