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Food Chem Toxicol. 2019 Mar 6;127:53-60. doi: 10.1016/j.fct.2019.03.001. [Epub ahead of print]

Camptothecin induces c-Myc- and Sp1-mediated hTERT expression in LNCaP cells: Involvement of reactive oxygen species and PI3K/Akt.

Author information

1
Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
2
Department of Bioprocess Technology, Faculty of Technology, Rajarata University of Sri Lanka, Mihintale 50300, Sri Lanka.
3
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea.
4
Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr.

Abstract

Camptothecin (CPT), a quinoline alkaloid isolated from Camptotheca acuminate, targets topoisomerase I, which is continuously expressed in cancer cells. However, the molecular mechanisms responsible for CPT-induced telomerase inhibition remain unclear. Unexpectedly, we found that CPT upregulates hTERT expression and concomitantly increases telomerase activity. However, transfection of hTERT-targeting siRNA had no effect on CPT-induced G2/M phase arrest, suggesting that CPT-induced telomerase activation was not related to G2/M phase arrest. CPT simultaneously increased Nrf2 expression and the level of intracellular reactive oxygen species (ROS), whereas pretreatment with the antioxidants N-acetyl-cysteine (NAC) or glutathione (GSH) strongly attenuated ROS production, which was accompanied by hTERT downregulation. Additionally, transient Nrf2 knockdown enhanced CPT-induced ROS production and hTERT promoter activity. CPT also upregulated hTERT expression and telomerase activity by inducing c-Myc and Sp1 expression and activity. Moreover, c-Myc stimulated ROS production in response to CPT, leading to Sp1 activation, which promoted hTERT expression and telomerase activity. CPT treatment enhanced the phosphorylation of PI3K and Akt, which led to hTERT phosphorylation into the nucleus. These findings demonstrate that CPT positively regulates telomerase activity by upregulating hTERT expression and phosphorylation via the c-Myc/ROS/Sp1 and PI3K/Akt axis.

KEYWORDS:

Camptothecin; ROS; Sp1; Telomerase; c-Myc; hTERT

PMID:
30851366
DOI:
10.1016/j.fct.2019.03.001

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