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.