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The hidden role of paxillin: localization to nucleus promotes tumor angiogenesis

Oncogene volume 40, pages 384–395 (2021)Cite this article

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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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Fig. 1: Increased PXN expression in ovarian cancer.
Fig. 2: Decreased Src expression in siPXN-treated ovarian cancer cells.
Fig. 3: PXN is a transcription factor for SRC.
Fig. 4: CRM1 is associated with PXN transport.
Fig. 5: NF-ĸB activation induces PLAT expression.
Fig. 6: PXN silencing in a mouse model of ovarian cancer.

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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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  1. These authors contributed equally: Kyunghee Noh, Duc-Hiep Bach

Authors and Affiliations

  1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Kyunghee Noh, Duc-Hiep Bach, Hyun-Jin Choi, Mark S. Kim, Sherry Y. Wu, Sunila Pradeep, Emine Bayraktar, Santosh K. Dasari, Elaine Stur, Lingegowda S. Mangala & Anil K. Sood

  2. Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Daejeon, Republic of Korea

    Kyunghee Noh

  3. Department of Obstetrics and Gynecology, Chung-Ang University College of Medicine, Seoul, Republic of Korea

    Hyun-Jin Choi

  4. Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Cristina Ivan, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Gabriel Lopez-Berestein & Anil K. Sood

  5. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Cristina Ivan, Cristian Rodriguez-Aguayo & Gabriel Lopez-Berestein

  6. Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Min-Soon Cho

  7. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Anil K. Sood

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Contributions

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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Correspondence to Anil K. Sood.

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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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