Abstract
Telomerase, a ribonucleoprotein reverse transcriptase that extends telomeres of eukaryotic chromosomes is repressed in normal somatic cells but is activated during development and neoplasia. The regulation mechanism of telomerase activity in cancer cells is not clearly known. In this report, a possible affect of PKC on telomerase activity was examined using HeLa and CUMC-6 cervical cancer cell lines. Exposure of cells to PKC inhibitor, bisindolylmaleimide I and Gö6976, and high levels of PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA) resulted in the inhibition of PKC activity in both cells. Telomerase activities were also inhibited by bisindolyl-maleimide I and Gö6976, respectively, in a time-dependent manner. As PKC activity changes in TPA-treated cervical cancer cells, telomerase activities were increased at low dose of TPA and decreased at high dose. The expression levels of human telomerase subunits, human telomerase RNA (hTR) were not influenced by PKC modulating drugs. In contrast, the expression of full-length human telomerase reverse transcriptase (hTERT) was decreased after exposure to bisindolylmaleimide I and Gö6976 in a time-dependent manner. hTERT expression was not affected by low dose of TPA. In contrast, high dose of TPA inhibited hTERT expression level. But the expression patterns of beta-deletion transcript of hTERT after 72 h of treatment with PKC inhibitors or high dose of TPA exposure were not discernable as compared with those of full-length hTERT transcripts to PKC modulating drugs. These results suggest that PKC-modulating drugs altered telomerase activities by affecting full-length hTERT expression profile in human cervical cancers.
Highlights
Telomerase, a specialized ribonucleoprotein reverse transcriptase that extends hexanucleotides (TTAGGG) telomeres onto chromosomal ends is repressed in normal somatic cells but is activated during development and neoplasia
tetradecanoyl phorbol 13-acetate (TPA) is an activator of protein kinase C (PKC) activity, it has previously been shown that TPA at maximal or submaximal concentration elicits down-regulation of PKC in response to continuous stimulation (Blobe et al, 1996; Liu, 1996)
Telomerase activity after 24 h of treatment with 1 μM TPA was significantly decreased in both cell lines. These results showed that the inhibition of telomerase activity with bisindolylmaleimide I, Gö6976 and high dose (1 μM) of TPA, and the activation of telomerase activity with low dose (10 nM) of TPA corresponded to the PKC activity changes
Summary
Telomerase, a specialized ribonucleoprotein reverse transcriptase that extends hexanucleotides (TTAGGG) telomeres onto chromosomal ends is repressed in normal somatic cells but is activated during development and neoplasia. Telomerase activity has been detected in germline cells (Meeker and Coffey, 1997) and in the majority of immortal and tumor cells (Shay and Bacchetti, 1997; Park et al, 1998), but not in normal somatic cells except in some self-renewing cells with high regenerative potential such as hematopoietic (Hiyama et al, 1995) and endometrial cells (Kyo et al, 1997). These findings have led to the hypothesis that telomerase reactivation represents a critical step in the neoplastic process. Little is known concerning the molecular mechanisms by which telomerase is activated in human tumors
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