Abstract
Chemotherapy is an important option for the treatment of various cancers including lung cancer. However, tumor resistance towards cytotoxic chemotherapy has become more common. It has been reported that autophagy is one of the processes contributing to this resistance. In the present study, we found that the anti-cancer drug 5-fluorouraci(5-FU) could induce autophagy in A549 cells. 5-FU treatment could lead to the conversion of LC3 I/II, the up-regulation of Beclin-1, the down-regulation of p62 and the formation of acidic vesicular organelles (AVOs) in A549 cells. Pre-treatment of cancer cells with 3-MA or siAtg7 could enhance 5-FU-induced apoptosis through the activation of caspases, and the caspase inhibitor z-VAD-fmk rescued the cell viability reduction. Furthermore, the inhibition of autophagy also stimulated ROS formation and scavenging of ROS by antioxidant NAC inhibited caspase-3 activity, prevented the release of cyt-c from mitochondria and eventually rescued cancer cells from 5-FU-mediated apoptosis. These results suggest that 5-FU-elicited autophagic response plays a protective role against cell apoptosis and the inhibition of autophagy could sensitize them to 5-FU-induced caspase-dependent apoptosis through the stimulation of ROS formation.
Highlights
Lung cancer is one of the most common malignancies in the world and the leading cause of cancer-related death in many countries
In the past years, mounting evidence indicates that reactive oxygen species (ROS) are implicated in autophagy induction in cancer therapy [19,20,21], suggesting that ROS play a crucial role in response to cancer therapeutics, deregulation of ROS formation is associated with cancer initiation, progression and drug resistance
We demonstrated the mechanism that autophagy inhibition sensitized cell to apoptotic cell death was by increasing the formation of ROS that eventually facilitated the release of cytochrome c from mitochondria, which subsequently enhanced caspase-dependent apoptosis
Summary
Lung cancer is one of the most common malignancies in the world and the leading cause of cancer-related death in many countries. Appropriate modification of autophagy, inhibition of cytoprotective autophagy to enhance the apoptosis of tumor cells in response to anti-cancer agents might improve the effects of chemotherapy [9]. In addition to apoptotic response, the study of autophagy is a prospective direction for the development of anti-cancer drugs. In the past years, mounting evidence indicates that ROS are implicated in autophagy induction in cancer therapy [19,20,21], suggesting that ROS play a crucial role in response to cancer therapeutics, deregulation of ROS formation is associated with cancer initiation, progression and drug resistance. We demonstrated the mechanism that autophagy inhibition sensitized cell to apoptotic cell death was by increasing the formation of ROS that eventually facilitated the release of cytochrome c from mitochondria, which subsequently enhanced caspase-dependent apoptosis
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