Abstract 2978: Extracellular ATP induced senescence in human lung cancer cells

Abstract

Abstract In tumors, extracellular ATP (eATP) concentrations are 1,000 to 10,000 times higher than is found in normal tissues and eATP is up taken through macropinocytosis leading to a large increase in intracellular ATP levels. eATP is also linked to the TGF-β signaling pathway as exocytosis of ATP is induced that is then used in an autocrine fashion activating the P2 × 7 purinergic receptor1. Through these mechanisms, eATP has also been recently shown to induce EMT, CSC formation, and drug resistance1. One of the mechanisms through which these processes may be induced is a senescent cell precursor2. Senescence is a generally irreversible epigenetically controlled process characterized by a complete exit from the cell cycle in response to either DNA damage, stressful conditions, or aging. Recent mounting evidence has shown that senescence can be a cancer promoting mechanism by entering this state in response to stress such as during chemotherapy, but they can utilize it to enhance their malignant capabilities, including the ability to escape their senescent state with heightened stem cell characteristics, which can lead to a higher chance of relapse after treatment2. Senescent cells have recently been named a hallmark of cancer3. This study shows the time dependent induction of a senescent like state in human lung cancer A549 cells after only 2 hours of treatment with 0.5mM eATP, the concentration found in the tumor microenvironment, through analysis of transcriptional markers using total polyA RNAseq as well as chromogenic and flow cytometric assays for senescence associated beta-galactosidase activity. Additionally, inhibitors of macropinocytosis and purinergic receptors have been used to gain insight into the mechanisms of action that this pathway takes. This demonstrates a novel use of ATP within the tumor microenvironment for aiding in cancer progression and drug resistance. After EMT, CSC formation, and drug resistance, senescence is added to the long list of eATP mediated cancer promoting processes. 1. Song J, Qian Y, Evers M, Nielsen CM, Chen X. Cancer Stem Cell Formation Induced and Regulated by Extracellular ATP and Stanniocalcin-1 in Human Lung Cancer Cells and Tumors. IJMS. 2022;23(23):14770. doi:10.3390/ijms232314770 2. Zhang D, Monteiro MJ, Liu J, Gu W. Mechanisms of cancer stem cell senescence: Current understanding and future perspectives. Clin Exp Pharma Physio. 2021;48(9):1185-1202. doi:10.1111/1440-1681.13528 3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Citation Format: Ryan A. Ward, Arabella Hunt, Nora Anderson, Xiaozhuo Chen. Extracellular ATP induced senescence in human lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2978.