Journal
ONCOTARGET
Volume 8, Issue 17, Pages 28342-28358Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16058
Keywords
artocarpin; pro-oxidation; lung cancer; p53; apoptosis
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Funding
- Chang Gung Medical Research Program Foundation [CMRPGMC0011, CMRPGMC0012, CMRPF6F0011]
- Ministry of Science and Technology of Taiwan [MOST 105-2320-B-255-002]
- China Medical University Hospital [DMR-105-074, DMR-106-038, DMR-102-069]
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Artocarpin has been shown to exhibit cytotoxic effects on different cancer cells, including non-small cell lung carcinoma (NSCLC, A549). However, the underlying mechanisms remain unclear. Here, we explore both p53-dependent and independent apoptosis pathways in artocarpin-treated NSCLC cells. Our results showed that artocarpin rapidly induced activation of cellular protein kinases including Erk1/2, p38 and Akt(S473). Inhibition of these protein kinases prevented artocarpin-induced cell death. Moreover, artocarpin-induced phosphorylation of these protein kinases and apoptosis were mediated by induction of reactive oxygen species (ROS), as pretreatment with NAC (a ROS scavenger) and Apocynin (a Nox-2 inhibitor) blocked these events. Similarly, transient transfection of p47(Phox) or p91(Phox) siRNA attenuated artocarpin-induced NADPH oxidase activity and cell death. In addition, p53 dependent apoptotic proteins including PUMA, cytochrome c, Apaf-1 and caspase 3 were activated by artocarpin, and these effects can be abolished by antioxidants, MAPK inhibitors (U0126 and SB202190), but not by PI3K inhibitor (LY294002). Furthermore, we found that artocarpin-induced Akt phosphorylation led to increased NF-kappa B activity, which may act as an upstream regulator in the c-Myc and Noxa pathway. Therefore, we propose that enhancement of both ERK/p38/p53-dependent or independent AktS473/NF-kappa B/c-Myc/Noxa cascade by Nox-derived ROS generation plays an important role in artocarpin-induced apoptosis in NSCLC cells.
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