Abstract
Cordycepin, a main active composition extracted from Cordyceps militaris, has been reported to exert anti-tumor activity in a broad spectrum of cancer types. However, the function of cordycepin on human non-small cell lung cancer cells is still obscure. Our present work showed that cordycepin inhibited cell growth by inducing apoptosis and autophagy in human NSCLC cells. Further study revealed that cordycepin triggered extrinsic apoptosis associated with down-regulation of c-FLIPL which suppresses the activity of caspase-8. And ectopic expression of c-FLIPL dramatically prevented cordycepin-caused apoptosis. Meanwhile, cordycepin stimulated autophagy through suppressing mTOR signaling pathway in lung cancer cells. When autophagy was blocked by Atg5 siRNA or PI3K inhibitor LY294002, the levels of apoptosis caused by cordycepin were obviously attenuated. In addition, suppression of autophagy could also elevate the level of c-FLIPL which indicated cordycepin-triggered autophagy promoted the degradation of c-FLIPL. Therefore, we conclude that cordycepin induces apoptosis through autophagy-mediated downregulation of c-FLIPL in human NSCLC cells. Taken together, our findings provide a novel prospect on the anti-tumor property of cordycepin, which may further prompt cordycepin to serve as a promising therapeutic approach in NSCLC treatment.
Highlights
Lung cancer has been a disastrous malignant neoplasm with highest incidence and mortality all over the world, which represents a poor five-year survival rate of less than 15% [1]
To illuminate the mechanism that cordycepin caused survival suppression in human non-small cell lung cancer (NSCLC) cells, flow cytometry analysis was performed to examine the impact of cordycepin on apoptosis and the data revealed that cordycepin dramatically increased the percentage of early and late apoptotic cells in H1299 and H460 after treated with increasing dosage of cordycepin for 24 h (Figure 1B)
Afterwards, we carried out western blot assay to detect whether cordycepin triggered caspase-dependent apoptosis and found that the cleaved forms of caspase-8, caspase-9, caspase-3 and poly ADP-ribose polymerase (PARP) were significantly elevated both in a dose-dependent manner (Figure 1C)
Summary
Lung cancer has been a disastrous malignant neoplasm with highest incidence and mortality all over the world, which represents a poor five-year survival rate of less than 15% [1]. It is extraordinarily urgent to develop and exploit novel anticancer agents to improve its clinical outcomes. Natural agents have attracted much attention for cancer treatment. Cordycepin (3'-deoxyadenosine), a natural product derived from Cordyceps sinensis, has been widely used in Chinese traditional medicine. Cordycepin possesses multiple pharmacological properties, such as anti-fungal, antibacterial, anti-inflammatory and anti-tumor effects [2, 3]. Cordycepin inhibits cancer cell growth through cell cycle arrest and apoptosis induction [5]. Ames and subacute toxicity test showed that cordycepin exhibited non-mutagenic and non-toxic property in rat model by oral administration [6]. The effects of cordycepin on human NSCLC cells have not been deeply investigated
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