Telomerase activity is suppressed in normal somatic tissues but is activated in most
cancer cells. We have previously found that all six
telomerase subunit
proteins, including hTERT and hsp90 are needed for full
enzyme activity.
Telomerase activity has been reported to be upregulated by
protein kinase C (PKC), but the mechanism is not clear. In this study, we examined how PKC regulates
telomerase activity in
head and neck cancer cells. PKC inhibitor,
bisindolylmaleimide I (BIS), inhibited
telomerase activity but had no effect on the expressions of
telomerase core subunits. RNA interference (RNAi) and in vitro phosphorylation studies revealed that PKC
isoforms alpha, beta, delta, epsilon, zeta specifically involved in
telomerase regulation, and the phosphorylation target was on hTERT. Treatment with the hsp-90 inhibitor
novobiocin dissociated hsp90 and hTERT as revealed by immunoprecipitation and immunoblot analysis and reduced
telomerase activity. Treatment with the PKC activator
SC-10 restored the association of hsp90 and hTERT and reactivate
telomerase, suggesting that hTERT phosphorylation by PKC is essential for
telomerase holoenzyme integrity and function. Analysis on clinical normal and tumour tissues reveal that the expressions of PKC alpha, beta, delta, epsilon, zeta were higher in the tumour tissues, correlated with
telomerase activity. Disruption of PKC phosphorylation by BIS significantly increased chemosensitivity to
cisplatin. In conclusion, PKC
isoenzymes alpha, beta, delta, epsilon, zeta regulate
telomerase activity in
head and neck cancer cells by phosphorylating hTERT. This phosphorylation is essential for
telomerase holoenzyme assembly, leading to
telomerase activation and
oncogenesis. Manipulation of
telomerase activity by PKC inhibitors is worth exploring as an adjuvant therapeutic approach.