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p53, secreted by K-Ras–Snail pathway, is endocytosed by K-Ras-mutated cells; implication of target-specific drug delivery and early diagnostic marker

Abstract

p53 is eliminated from K-Ras-mutated cancer cells through direct interaction with Snail. However, it is not achieved through proteasome-mediated degradation or transcriptional repression. Here we provide evidence that p53, binding with Snail, is exported from a K-Ras-mutated cell through a vesicle transport-like mechanism, independently using a p53-nuclear-exporting mechanism. Although we can detect p53 in culture media, a majority of p53 might be degraded by extracellular proteases. Thus, we can recover the secreted p53 in culture media by the inhibition of protease and endocytosis. In addition, a considerable amount of p53 is endocytosed by neighboring cells. As p53 resorption occurs in a K-Ras-dependent manner, treatment of recombinant p53 is detected in the whole-cell lysate of K-Ras-mutated cells, but not in that of wild-type cells. Using the property of p53, we can deliver the chemical (propidium iodine) into K-Ras mutated cells selectively. In contrast, Snail, a co-secreted protein with p53 in response to oncogenic K-Ras, shows resistance to endocytosis and protease, and results in remaining in the media. Thus, we can detect an autoantibody against Snail in the serum of a human cancer patient. Our finding can be used for a mutant K-Ras-specific anticancer drug delivery system and for the diagnosis of pancreatic, colon and lung cancers.

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Acknowledgements

This work was supported by a research grant from the Research Team for Longevity Life Sciences in Pusan National University and by the Bio-Scientific Research Grant funded by the Pusan National University (PNU, Bio-Scientific Research Grant) (PNU-2008-101-2008—596-000).

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Correspondence to B-J Park.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lee, SH., Lee, SJ., Chung, JY. et al. p53, secreted by K-Ras–Snail pathway, is endocytosed by K-Ras-mutated cells; implication of target-specific drug delivery and early diagnostic marker. Oncogene 28, 2005–2014 (2009). https://doi.org/10.1038/onc.2009.67

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