Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer and has been shown to be promising for treating various types of cancers. However, the application of TRAIL is greatly impeded by the resistance of cancer cells to its action. Studies show that overexpression of some critical pro-survival proteins, such as survivin, is responsible for TRAIL resistance. In this study, we found that Aplysin, a brominated compound from marine organisms, was able to restore the sensitivity of cancer cells to TRAIL both in vitro and in vivo. Aplysin was found to enhance the tumor-suppressing capacity of TRAIL on several TRAIL-resistant cancer cell lines. TRAIL-induced apoptosis was also potentiated in A549 and MCF7 cells treated with Aplysin. Survivin downregulation was identified as a mechanism by which Aplysin-mediated TRAIL sensitization of cancer cells. Furthermore, the activation of p38 MAPK was revealed in Aplysin-treated cancer cells, and its inhibitor SB203580 was able to abrogate the promoting effect of Aplysin on the response of cancer cells to TRAIL action, as evidenced by restored survivin expression, elevated cell survival and reduced apoptotic rates. In conclusion, we provided evidence that Aplysin acts as a sensitizer for TRAIL and its effect on p38 MAPK/survivin pathway may partially account for this activity. Considering its low cytotoxicity to normal cells, Aplysin may be a promising agent for cancer treatment in combination with TRAIL.
Highlights
TNF-related apoptosis-inducing ligand (TRAIL) is a cytokine that elicits programed cell death, apoptosis, in tumor cells
We found that Aplysin was able to enhance the anti-tumor activity of TRAIL on resistant cancer cell lines
P38 MAPK-dependent survivin downregulation in cancer cells is required for the synergistic effect of Aplysin on TRAIL action
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is a cytokine that elicits programed cell death, apoptosis, in tumor cells. Because of its tumor-specific apoptosis-inducing property, TRAIL has served as a biological agent of cancer treatment for decades [2], clinical trials have not shown significant survival benefit on cancer patients [3]. To change the response of intracellular molecules to TRAIL action, cancer cells minimize the expression of caspase proteins or elevate the level of pro-survival proteins, such as xIAP, cIAP or survivin [5]. Natural or synthetic compounds have been demonstrated to increase the responsiveness of cancer cells to TRAIL action by depleting survivin [9,10,11,12,13]. We found that Aplysin was able to enhance the anti-tumor activity of TRAIL on resistant cancer cell lines. P38 MAPK-dependent survivin downregulation in cancer cells is required for the synergistic effect of Aplysin on TRAIL action
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
