Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and is also highly resistant to conventional chemotherapy treatments. In this study, we report that Longikaurin A (LK-A), an ent-kaurane diterpenoid isolated from the plant Isodon ternifolius, induced cell cycle arrest and apoptosis in human HCC cell lines. LK-A also suppressed tumor growth in SMMC-7721 xenograft models, without inducing any notable major organ-related toxicity. LK-A treatment led to reduced expression of the proto-oncogene S phase kinase-associated protein 2 (Skp2) in SMMC-7721 cells. Lower Skp2 levels correlated with increased expression of p21 and p-cdc2 (Try15), and a corresponding decrease in protein levels of Cyclin B1 and cdc2. Overexpression of Skp2 significantly inhibited LK-A-induced cell cycle arrest in SMMC-7721 cells, suggesting that LK-A may target Skp2 to arrest cells at the G2/M phase. LK-A also induced reactive oxygen species (ROS) production and apoptosis in SMMC-7721 cells. LK-A induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase and P38 MAP kinase. Treatment with, the JNK inhibitor SP600125 prevented LK-A-induced apoptosis in SMMC-7721 cells. Moreover, the antioxidant N-acetylcysteine prevented phosphorylation of both JNK and c-Jun. Taken together, these data indicate that LK-A induces cell cycle arrest and apoptosis in cancer cells by dampening Skp2 expression, and thereby activating the ROS/JNK/c-Jun signaling pathways. LK-A is therefore a potential lead compound for development of antitumor drugs targeting HCC.

ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer

“…Overproduced ROS and free radicals lead to serious damage to lipids, proteins, and DNA, and regulate the process involved in the initiation of apoptotic signaling [29, 36]. ROS overproduction could induce the depolarization of the mitochondrial membrane, which eventually results in an increase in the level of other pro-apoptotic molecules in the cytosol [37].…”

Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP

“…At the initial stage in HCC development, ROS or oxidative stress-responses mainly stimulate hepatocarcinogenesis or promote HCC development by activating pro-oncogenic gene activities or oncogenic signaling pathways such as mitogen-activated protein kinases (MAPKs) [3, 4]. Along with the progression of HCC, ROS overproduction or long-lasting oxidative stress-responses would tend to induce cell death or prevent cancer development in HCC [1, 5]. Therefore, modulating homeostasis of ROS or oxidative stress-responses has become an important therapeutic strategy for HCC [5, 6].…”

“…Along with the progression of HCC, ROS overproduction or long-lasting oxidative stress-responses would tend to induce cell death or prevent cancer development in HCC [1, 5]. Therefore, modulating homeostasis of ROS or oxidative stress-responses has become an important therapeutic strategy for HCC [5, 6]. Accumulative evidences support that oxidants have therapeutic effects in cancer treatment and the underlying mechanisms have been well studied [5, 7-11].…”

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

“…It has been reported that ent-kaurane diterpenoids exhibit cytotoxic effects with the induction of ROS [23,24,33] . Consistently with the observations that oridonin and longikaurin A induce ROS-dependent inhibitory effects on cell proliferation, our study demonstrated that both JA and JB induced ROS production, which in turn led to the DNA damage response.…”