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

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.

• Authors: Matharage Gayani Dilshara, Rajapaksha Gedara Prasad Tharanga Jayasooriya, Yung Hyun Choi, Gi-Young Kim
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 127 Pg. 53-60 (May 2019) ISSN: 1873-6351 [Electronic] England
• PMID: 30851366 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Sp1 Transcription Factor
• Topoisomerase I Inhibitors
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• TERT protein, human
• Telomerase
• Camptothecin

Topics

• Camptothecin (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Enzyme Activation
• Genes, myc
• Humans
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sp1 Transcription Factor (metabolism)
• Telomerase (metabolism)
• Topoisomerase I Inhibitors (pharmacology)