Title of the paper: Role of p53 transcription factor in determining the efficacy of telomerase inhibitors in cancer treatment
Author Names: Kavita Gala, Meghna Jain, Prachi Shah, Amit Pandey, Manoj Garg, Ekta Khattar*
Journal name, Pages, Vol, Year: Life Sciences, Article 122416, Volume 339, 2024.
Impact Factor: 6.1
Link of the article: https://doi.org/10.1016/j.lfs.2024.122416
Abstract:
Aim
Telomerase expression is unique to cancer cells, making it a promising target for therapy. However, a major drawback of telomerase inhibition is that it affects cancer cell proliferation only when telomeres shorten, creating a lag phase post-continuous drug treatment. Acute cytotoxicity of telomerase inhibitors is dependent on their ability to induce DNA damage. p53 senses DNA damage and is the primary effector required for sensitizing cells toward apoptosis.
Main methods
Isogenic p53+/+ and p53−/− ovarian cancer cell lines were generated using the CRISPR/Cas9 system and the anti-cancer effect of telomerase inhibitors MST-312 and BIBR1532 were determined. Flow cytometry, real-time PCR, and western blot were performed to study cell cycle, apoptosis, and gene expression.
Key findings
We report that MST-312 exhibits p53-dependent cytotoxicity, while BIBR1532 exhibits p53-independent cytotoxicity. Colony-forming ability also confirms the p53-dependent effect of MST-312. Re-expression of p53 in p53−/− cells could rescue MST-312 sensitivity. In p53+/+cells, MST-312 causes S phase arrest and activation of p53-dependent target genes like anti-apoptosis markers (Fas and Puma) and cell cycle markers (p21 and cyclin B). In p53−/− cells, MST-312 causes S/G2/M arrest. BIBR1532 induces S/G2/M phase cell cycle arrest irrespective of p53 status. This correlates with the expression of the DNA damage marker (γ-H2AX). Long-term continuous treatment with MST-312 or BIBR1532 results in p53-independent telomere shortening.
Significance
In summary, we demonstrate that acute anti-cancer effects of MST-312 are dependent on p53 expression. Hence, it is important to consider the p53 expression status in cancer cells when selecting and administering telomerase inhibitors.
