Open AccessSlug increases sensitivity to tubulin‐binding agents via the downregulation of βIII and βIVa‐tubulin in lung cancer cells
Author(s) -
Tamura Daisuke,
Arao Tokuzo,
Nagai Tomoyuki,
Kaneda Hiroyasu,
Aomatsu Keiichi,
Fujita Yoshihiko,
Matsumoto Kazuko,
Velasco Marco A.,
Kato Hiroaki,
Hayashi Hidetoshi,
Yoshida Shuhei,
Kimura Hideharu,
Maniwa Yoshimasa,
Nishio Wataru,
Sakai Yasuhiro,
Ohbayashi Chiho,
Kotani Yoshikazu,
Nishimura Yoshihiro,
Nishio Kazuto
Publication year - 2013
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.68
Subject(s) - slug , downregulation and upregulation , biology , cancer research , vinorelbine , paclitaxel , tubulin , microbiology and biotechnology , cancer , biochemistry , microtubule , chemotherapy , gene , cisplatin , genetics
Transcription factor Slug / SNAI 2 ( snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage‐independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin‐binding agents including vinorelbine, vincristine, and paclitaxel (5.8‐ to 8.9‐fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin‐binding agents. Real‐time RT ‐ PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of βIII and βIVa‐tubulin, which is considered to be a major factor determining sensitivity to tubulin‐binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of βIVa‐tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of βIII and βIV‐tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin‐binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin‐binding agents via the downregulation of βIII and βIVa‐tubulin in lung cancer cells.