Abstract
Paxillin (PXN), a key component of the focal adhesion complex, has been associated with cancer progression, but the underlying mechanisms are poorly understood. The purpose of this study was to elucidate mechanisms by which PXN affects cancer growth and progression, which we addressed using cancer patient data, cell lines, and orthotopic mouse models. We demonstrated a previously unrecognized mechanism whereby nuclear PXN enhances angiogenesis by transcriptionally regulating SRC expression. SRC, in turn, increases PLAT expression through NF-ĸB activation; PLAT promotes angiogenesis via LRP1 in endothelial cells. PXN silencing in ovarian cancer mouse models reduced angiogenesis, tumor growth, and metastasis. These findings provide a new understanding of the role of PXN in regulating tumor angiogenesis and growth.
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Acknowledgements
Portions of this work were supported by the National Institutes of Health (P30 CA016672, P50 CA217685, P50 CA098258, and R35 CA209904), the Blanton-Davis Ovarian Cancer Research Program, American Cancer Society Research Professor Award, Judy’s Mission, and the Frank McGraw Memorial Chair in Cancer Research. SP is supported by the Ovarian Cancer Research Fund Alliance (OCRFA). ES is supported by Ovarian Cancer Research Alliance (OCRA number FP00006137). KHN is supported by the KRIBB Research Initiative Program. We thank Dr. Bryan F. Tutt (Department of Scientific Publications) and Nicholas B. Jennings for kindly reviewing this manuscript.
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KHN, D-HB, H-JC, and MSK designed the experiments. KHN, D-HB, and H-JC performed the experiments, analyzed data, and wrote the manuscript; SYW, MSK, SP, IC, M-SC, RR, CR-A, RAP, SKD, ES, and LSM performed experiments and analyzed data. GLB discussed and contributed to data. AKS supervised the entire project, designed the experiments, analyzed data, and revised the manuscript.
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AKS (consulting for Kiyatec and Merck; research funding from M-Trap; stockholder in BioPath).
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Noh, K., Bach, DH., Choi, HJ. et al. The hidden role of paxillin: localization to nucleus promotes tumor angiogenesis. Oncogene 40, 384–395 (2021). https://doi.org/10.1038/s41388-020-01517-3
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DOI: https://doi.org/10.1038/s41388-020-01517-3
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