Abstract
Cucurbitacins are a class of triterpenoids widely distributed in plant kingdom with potent anti-cancer activities both in vitro and in vivo by inducing cycle arrest, autophagy, and apoptosis. Cucurbitacin B (Cuc B), could induce S or G2/M cell cycle arrest in cancer cells while the detailed mechanisms remain to be clear. This study was designed to precisely dissect the signaling pathway(s) responsible for Cuc B induced cell cycle arrest in human lung adenocarcinoma epithelial A549 cells. We demonstrated that low concentrations of Cuc B dramatically induced G2/M phase arrest in A549 cells. Cuc B treatment caused DNA double-strand breaks (DSBs) without affecting the signal transducer and activator of transcription 3 (STAT3), the potential molecular target for Cuc B. Cuc B triggers ATM-activated Chk1-Cdc25C-Cdk1, which could be reversed by both ATM siRNA and Chk1 siRNA. Cuc B also triggers ATM-activated p53-14-3-3-σ pathways, which could be reversed by ATM siRNA. Cuc B treatment also led to increased intracellular reactive oxygen species (ROS) formation, which was inhibited by N-acetyl-l-cysteine (NAC) pretreatment. Furthermore, NAC pretreatment inhibited Cuc B induced DNA damage and G2/M phase arrest. Taken together, these results suggested that Cuc B induces DNA damage in A549 cells mediated by increasing intracellular ROS formation, which lead to G2/M cell phase arrest through ATM-activated Chk1-Cdc25C-Cdk1 and p53-14-3-3-σ parallel branches. These observations provide novel mechanisms and potential targets for better understanding of the anti-cancer mechanisms of cucurbitacins.
Highlights
Cucurbitacins, a class of highly oxidized tetracyclic triterpenoids, are widely distributed in the plant kingdom
We demonstrated that Cucurbitacin B (Cuc B) causes G2/M phase cell cycle arrest in A549 cells, which is associated with DNA damage mediated by ATM-activated Chk1-Cdc25C-Cdk1 and p53-14-3-3-s parallel branches
We observed that Cuc B significantly inhibit A549 cell proliferation in a dose- and time- dependent manner (Fig. S1)
Summary
Cucurbitacins, a class of highly oxidized tetracyclic triterpenoids, are widely distributed in the plant kingdom. More than one hundred cucurbitacins and their derivatives have been identified while only a few of them have been widely investigated. Recent advances showed that cucurbitacins are potent anti-cancer natural products in both in vitro and in vivo models. Cucurbitacins dramatically inhibit the growth and proliferation of a series of cancer cells. They could induce cancer cell differentiation, inhibit angiogenesis and metastasis [2,3]. Previous studies showed that cucurbitacins significantly inhibited cell growth by interfering with actin dynamics [4,5,6,7]. Cucurbitacins have been identified as small molecular inhibitors of signal transduction and activator of transcription-3 (STAT3) [8,9,10]. F-actin and STAT3 have been generally considered as their potential molecular targets in cancer cells
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