Telomerase inhibition strategies by siRNAs against either hTR or hTERT in oral squamous cell carcinoma

Abstract

Human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) are considered effective molecular targets for current anticancer therapy. In this study, we investigated the therapeutic effects of targeting hTR and hTERT individually or in combination by recombinant adenovirus-delivered small interfering RNA (siRNA) in oral squamous cell carcinoma (OSCC) Tca8113. Further, we screened the optimal strategy for RNA interference. Our results show that these different recombinant adenoviruses specifically reduced the levels of hTR mRNA, hTERT mRNA, hTERT protein and telomerase activity in Tca8113 cells. Moreover, they successfully inhibited xenograft tumor growth in nude mice. The potency of their antitumor activities was ranked as follows: anti-hTR 4anti-hTR þ anti-hTERT 4anti-hTERT. Therefore, we demonstrated that the siRNA-expressing recombinant adenoviruses were an effective anticancer tool for treatment of OSCC. Furthermore, the anticancer effect of solely targeting hTR was more direct and efficient, compared with the effect of targeting hTR and hTERT in combination, or hTERT exclusively. The mechanism of this anticancer effect in OSCC was not only related to the inhibition of cell proliferation and the induction of cell apoptosis, but might also involve the inhibition of tumor angiogenesis.

MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer

“…Using a combination of two different siRNAs, we found that TERC knockdown elicits significant growth inhibition in PCa cell lines. In the past, several studies have targeted TERC with RNAi , which has consistently shown a reduced growth rate in different types of cancer cell lines and inhibited xenograft tumor growth in mice . The inhibitory effect on cell proliferation that we noticed was modest, which is in keeping with previous reports including one with PCa cell line .…”

Targeting EBV-LMP1 DNAzyme enhances radiosensitivity of nasopharyngeal carcinoma cells by inhibiting telomerase activity

“…16,17,28 The abnormally active telomerase in cancer cells has become one of the most interesting targets aimed at finding a cure for many different cancers. [29][30][31] LMP1 expression in NPC cells may mimic the effects of growth factors by activating telomerase via Akt, thus contributing to cell radioresistance.…”

Silencing of the hTERT Gene by shRNA Inhibits Colon Cancer SW480 Cell Growth In Vitro and In Vivo

“…Therefore future work should determine how best to deliver the siRNAs to tumor cells in the clinic. Formulating the siRNA with bioreducible cationic polymers, for example, shows substantial promise [45], [33], as does packaging in adenovirus [31]. Combining siRNA against hTERT with other therapies, such as radiation treatment [46], may also be appropriate.…”