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  3. Cell softening in malignant progression of human lung cancer cells by activation of receptor tyrosine kinase AXL

Cell softening in malignant progression of human lung cancer cells by activation of receptor tyrosine kinase AXL

  • Sci Rep. 2017 Dec 19;7(1):17770. doi: 10.1038/s41598-017-18120-4.
Keisuke Iida 1 2 3,  Ryo Sakai 1 2,  Shota Yokoyama 1 2,  Naritaka Kobayashi 1,  Shodai Togo 4,  Hiroshi Y Yoshikawa 4,  Anchalee Rawangkan 1 2,  Kozue Namiki 1 2,  Masami Suganuma 5 6
Affiliations

Affiliations

  • 1 Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama, 338-8570, Japan.
  • 2 Research Institute for Clinical Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, 362-0806, Japan.
  • 3 Molecular Chirality Research Center and Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba, 263-8522, Japan.
  • 4 Department of Chemistry, Saitama University, Sakura-ku, Saitama, 338-8570, Japan.
  • 5 Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama, 338-8570, Japan. masami0306@mail.saitama-u.ac.jp.
  • 6 Research Institute for Clinical Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, 362-0806, Japan. masami0306@mail.saitama-u.ac.jp.
PMID: 29259259 DOI: 10.1038/s41598-017-18120-4
Abstract

To study the role of cell softening in malignant progression, Transwell assay and atomic force microscope were used to classify six human non-small cell lung Cancer cell lines into two groups: a high motility-low stiffness (HMLS) group and a low motility-high stiffness (LMHS) group. We found a significant role of activity of the Axl receptor tyrosine kinase, which belongs to the TAM (TYRO3, Axl, Mer) family, in the stimulation of motility and cell softening. HMLS cells expressed higher Axl levels than LMHS cells and contained phosphorylated Axl. H1703 LMHS cells transfected with exogenous Axl exhibited increased motility and decreased stiffness, with low levels of actin stress fibre formation. Conversely, the AXL-specific inhibitor R428 and AXL-targeting siRNA reduced motility and increased stiffness in H1299 HMLS cells. Knockdown of Axl stimulated actin stress fibre formation, which inhibited tumour formation in a mouse xenograft model. The Ras/Rac inhibitor SCH 51344, which blocks disruption of actin stress fibres, exerted similar effects to Axl inactivation. We therefore propose that the Ras/Rac pathway operates downstream of Axl. Thus, Axl activation-induced cell softening promotes malignant progression in non-small cell lung Cancer and represents a key biophysical property of Cancer cells.

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