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Abstract
The transcription factor p53 is frequently lost during tumor development in solid tumors; however, most melanomas retain a wild type p53 protein. The presence of wild type p53 in melanoma has fueled speculation that p53 may play a neutral or pro-tumorigenic role in this disease. Here we show that p53 is functional in human melanoma cell lines, and that loss of p53 results in a general reduction in basal NF-kB regulated cytokine production. The reduced cytokine expression triggered by p53 loss is broad and includes key inflammatory chemokines, such as CXCL1, CXCL8, and the IL6 class cytokine LIF, resulting in a reduced ability to induce chemotactic-dependent migration of tumor cells and immune cells and increased sensitivity to BRAF inhibition. Taken together, this result indicates that wild type p53 regulates cytokine expression and induces cytokine-dependent phenotype on melanoma.
Highlights
The pleiotropic transcription factor p53 is a tumor suppressor that is frequently lost in human cancer development [1]
We observed that p53 could associate with cytokine genes such as IL1A and CXCL1 in certain melanoma cell lines [9], and other groups have shown an association between p53 status and cytokine secretion in fibroblasts [10] and macrophages [11]
Though p53 levels rise in response to treatment, it is possible that p53 signaling in these models is defective for the transcriptional activation of key cell cycle arrest or pro-apoptosis target genes
Summary
The pleiotropic transcription factor p53 is a tumor suppressor that is frequently lost in human cancer development [1]. These p53 mutations are not associated with reduced survival [4,5], and melanoma is relatively rare in families with germline p53 mutations [6,7] These features of melanoma have fueled speculation that p53 may play a complex and potentially pro-tumor role in this cancer through the regulation of cell cycle arrest [8]. We observed that p53 could associate with cytokine genes such as IL1A and CXCL1 in certain melanoma cell lines [9], and other groups have shown an association between p53 status and cytokine secretion in fibroblasts [10] and macrophages [11] This suggested to us that in melanoma p53 could potentially regulate—directly or in partnership with other factors—the expression of key immune-regulatory cytokines. We set out to test if loss of p53 would reduce the ability of melanoma cells to secrete cytokines and resist therapy
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