Camptothecin promotes the production of nitric oxide that triggers subsequent S-nitrosoproteome-mediated signaling cascades in endothelial cells

- CPT can phosphorylate the LKB1-AMPK-eNOS cascade.
- CPT-induced 726 S-nitrosoproteins were firstly identified.
- CPT increased the phosphorylation of p38 MAPK Thr180/Tyr182 and decreased the phosphorylation of Tau Ser199/202.
- Expression of inflammatory proteins was inhibited by CPT.
- CPT provides vascular homeostasis at low concentrations.

Camptothecin (CPT) has been used for colorectal cancer therapy. At low concentration of 10− 9 M, CPT modulates endothelial nitric oxide production following the phosphorylation of LKB1 Ser431, AMPK-α Thr172, eNOS Ser633 and Ser1177. Elevated nitric oxide (NO) was observed by FA-OMe fluorescent probe. 726 S-nitrosoproteins were identified by iTRAQ quantitative proteomics. IPA analysis indicated that ERK/MAPK was closely linked in the signaling network. Further studies showed that CPT phosphorylated p38 MAPK Thr180/Tyr182 and dephosphorylated Tau Ser199/202. CPT also suppressed the TNF-α-induced expression of the inflammasome and cyclooxygenase 2. All this suggests that in addition to the original character of CPT in attenuating the binding of topoisomerase I and DNA in cancer cells, the role of CPT in triggering NO production and the subsequent S-nitrosylated signaling including anti-inflammatory effects in endothelial cells are proposed here. CPT, therefore, provides a potential application addition in preventing vascular disorders.

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