title: Slug increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.
abstract: Transcription factor Slug/SNAI2 (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.
authors: Department of Genome Biology, Kinki University Faculty of Medicine Osaka, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine Kobe, Japan.
authors: Daisuke
authors: D
authors: Tamura
authors: Tokuzo
authors: T
authors: Arao
authors: Tomoyuki
authors: T
authors: Nagai
authors: Hiroyasu
authors: H
authors: Kaneda
authors: Keiichi
authors: K
authors: Aomatsu
authors: Yoshihiko
authors: Y
authors: Fujita
authors: Kazuko
authors: K
authors: Matsumoto
authors: Marco A
authors: MA
authors: De Velasco
authors: Hiroaki
authors: H
authors: Kato
authors: Hidetoshi
authors: H
authors: Hayashi
authors: Shuhei
authors: S
authors: Yoshida
authors: Hideharu
authors: H
authors: Kimura
authors: Yoshimasa
authors: Y
authors: Maniwa
authors: Wataru
authors: W
authors: Nishio
authors: Yasuhiro
authors: Y
authors: Sakai
authors: Chiho
authors: C
authors: Ohbayashi
authors: Yoshikazu
authors: Y
authors: Kotani
authors: Yoshihiro
authors: Y
authors: Nishimura
authors: Kazuto
authors: K
authors: Nishio
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014404:Tubulin / Q000096:biosynthesis / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C578986:TUBB1 protein, human; C576987:TUBB2B protein, human; C498585:TUBB3 protein, human; C582076:TUBB4A protein, human; D014157:Transcription Factors; D014404:Tubulin; D050257:Tubulin Modulators; D014750:Vincristine; D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine
keywords: Anoikis; lung cancer; slug; tubulin-binding agents; tumor growth
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