Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells.

Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy.

Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction.

Mitochondria are the most important sensor for apoptosis. Extracellular adenosine is well reported to induce apoptosis of tumor cells. Here we found that extracellular adenosine suppresses the cell growth by induction of apoptosis in BEL-7404 liver cancer cells, and identified a novel mechanism that extracellular adenosine triggers apoptosis by increasing Reactive Oxygen Species (ROS) production and mitochondrial membrane dysfunction in the cells. We observed that adenosine increases ROS production, activates c-Caspase-8 and -9 and Caspase effectors, c-Caspase-3 and c-PARP, induces accumulation of apoptosis regulator Bak, decreases Bcl-xL and Mcl-1, and causes the mitochondrial membrane dysfunction and the release of DIABLO, Cytochrome C, and AIF from mitochondria to cytoplasm in the cells; ROS inhibitor, NAC significantly reduces adenosine-induced ROS production; it also shows the same degree of blocking adenosine-induced loss of mitochondrial membrane potential (MMP) and apoptosis. Our study first observed that adenosine increases ROS production in tumor cells and identified the positive feedback loop for ROS-mediated mitochondrial membrane dysfunction which amplifies the death signals in the cells. Our findings indicated ROS production and mitochondrial dysfunction play a key role in adenosine-induced apoptosis of 7404 cells.

Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer.

Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC.