Abstract
BackgroundMetastatic melanoma is an aggressive form of skin cancer that evades various anti-cancer treatments including surgery, radio-,immuno- and chemo-therapy. TRAIL-induced apoptosis is a desirable method to treat melanoma since, unlike other treatments, it does not harm non-cancerous cells. The pro-inflammatory response to melanoma by nF κB and STAT3 pathways makes the cancer cells resist TRAIL-induced apoptosis. We show that due to to its dual action on DR5, a death receptor for TRAIL and on STAT3, Cryptotanshinone can be used to increase sensitivity to TRAIL.MethodsThe development of chemoresistance and invasive properties in melanoma cells involves several biological pathways. The key components of these pathways are represented as a Boolean network with multiple inputs and multiple outputs.ResultsThe possible mutations in genes that can lead to cancer are captured by faults in the combinatorial circuit and the model is used to theoretically predict the effectiveness of Cryptotanshinone for inducing apoptosis in melanoma cell lines. This prediction is experimentally validated by showing that Cryptotanshinone can cause enhanced cell death in A375 melanoma cells.ConclusionThe results presented in this paper facilitate a better understanding of melanoma drug resistance. Furthermore, this framework can be used to detect additional drug intervention points in the pathway that could amplify the action of Cryptotanshinone.
Highlights
Metastatic melanoma is an aggressive form of skin cancer that evades various anti-cancer treatments including surgery, radio,immuno- and chemo-therapy
TNF-related apoptosis-inducing ligand (TRAIL) resistance is observed in melanoma cell lines; it is associated with the mutations in cell survival pathways [3, 4]
We focus on the TRAIL apoptotic pathway and on the effect the genes in the other pathways have on extrinsic cell death
Summary
Metastatic melanoma is an aggressive form of skin cancer that evades various anti-cancer treatments including surgery, radio-,immuno- and chemo-therapy. TRAIL-induced apoptosis is a desirable method to treat melanoma since, unlike other treatments, it does not harm non-cancerous cells. The pro-inflammatory response to melanoma by nFκB and STAT3 pathways makes the cancer cells resist TRAIL-induced apoptosis. Melanoma is one of the most prevalent and aggressive forms of skin cancer. The chemoresistance of melanoma cell lines has been attributed to their inherent capability to survive. In melanoma cells in particular, and cancer cells in general, this survival mechanism is hijacked by the mutated genes and exploited to counter medical treatment [1]. TRAIL resistance is observed in melanoma cell lines; it is associated with the mutations in cell survival pathways [3, 4]
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