Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-Damage-Sensing-Dependent Cell Protection

Centeno, Daniel; Farsinejad, Sadaf; Kochetkova, Elena; Volpari, Tatiana; Gladych-Macioszek, Aleksandra; Klupczynska-Gabryszak, Agnieszka; Polotaye, Teagan; Greenberg, Michael; Kung, Douglas; Hyde, Emily; Alshehri, Sarah; Pavlovic, Tonja; Sullivan, William; Plewa, Szymon; Vakifahmetoglu-Norberg, Helin; Monsma, Frederick J.; Muller, Patricia A J; Matysiak, Jan; Zaborowski, Mikołaj Piotr; DiFeo, Analisa; Norberg, Erik; Martin, Laura A.; Iwanicki, Marcin

Abstract

Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine’s suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine’s ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine’s cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transduction.

Citation

Centeno, D., Farsinejad, S., Kochetkova, E., Volpari, T., Gladych-Macioszek, A., Klupczynska-Gabryszak, A., Polotaye, T., Greenberg, M., Kung, D., Hyde, E., Alshehri, S., Pavlovic, T., Sullivan, W., Plewa, S., Vakifahmetoglu-Norberg, H., Monsma, F. J., Muller, P. A. J., Matysiak, J., Zaborowski, M. P., DiFeo, A., …Iwanicki, M. (2024). Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-Damage-Sensing-Dependent Cell Protection. Nutrients, 16(12), Article 1816. https://doi.org/10.3390/nu16121816

• Journal Article Type: Article
• Acceptance Date: Jun 5, 2024
• Online Publication Date: Jun 9, 2024
• Publication Date: Jun 9, 2024
• Deposit Date: Jul 24, 2024
• Publicly Available Date: Jul 24, 2024
• Journal: Nutrients
• Electronic ISSN: 2072-6643
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 12
• Article Number: 1816
• DOI: https://doi.org/10.3390/nu16121816
• Keywords: taurine, signal transduction, genotoxic stress, fallopian tube cells, growth suppression, ovarian cancer cells, cell protection
• Public URL: https://durham-repository.worktribe.com/output/2526088