Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects

Abstract

Background:Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2.Methods:hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models.Results:Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo.Conclusion:hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells.

Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications

“…Consistently, Wu et al showed that BC cells with either −124C>T or −146C>T mutations acquired enhanced cellular motility [ 132 ]. In addition, TERT was further shown to protect cancer cells from apoptosis stimulated by various insults or stresses [ 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 ]. Taken together, the TERT promoter mutation enhances high TERT expression, thereby contributing to aggressive phenotypes of cancer cells and poor patient outcomes via both telomere lengthening-dependent and independent mechanisms.…”

Effects of Nonsteroidal Anti-inflammatory Drugs on the Self-renewal Capacity of Blast Progenitors in Hematological Malignancies

“…Although, in the present study, both agents markedly reduced telomerase activity in all seven cell lines, inhibition of SR was observed in only 4 (25%) out of 16 conditions. Telomerase inhibition results in stimulation of COX2 and mammalia target of rapamycin complex 1 and inhibition of autophagy (22,23). This may indicate that reduced telomerase activity may be necessary but not sufficient to inhibit SR capacity.…”

Effects of Resveratrol and Vitamin C on the Self-Renewal Capacity of Blast Progenitors in Hematologic Malignancies

“…This drives the prolonged expression of target genes critical for the maintenance of tumor survival and proliferation [53]. However, hTERT depletion alone did not affect cancer cell survival [54].…”