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.

Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133+ pancreatic cancer cells

“…On the other hand, it is reported that Slug increases sensitivity to tubulin-binding agents in lung cancer cells. Thus, the role of Slug in chemoresistance might depend on the type of drug [31].…”

TUBB4B Downregulation Is Critical for Increasing Migration of Metastatic Colon Cancer Cells

“…Changes of TUBB3 and TUBB4B levels have been studied with respect to the regulation of cancer progression [6]. Understanding of the well-characterized mechanism of decreased sensitivity of cancer cells to tubulin-binding agents (TBAs) like vinca alkaloids and taxanes, comes from the analysis of TUBB3 and TUBB4B level regulation in non-small cell lung cancer and prostate cancer development [12,13,14,15,16]. Additionally, TUBB3, TUBB4B, and TUBB6 downregulation were observed in taxane-resistant breast cancer cells [17].…”

Expression of ADP-ribosyltransferase 1 Is Associated with Poor Prognosis of Glioma Patients

“…Corresponding to our results, the in vivo study by also demonstrated that the proliferation effect of ART1 was more obvious under cisplatin stimulation compared with no stimulation. Similarly, several studies illustrated that TUBB3, which can regulate the cell sensitivity to tubulin-binding agents such as VCR, plays important roles in the drug-induced cell apoptosis and efficiency of chemotherapy in pancreatic cancer, breast cancer, and lung cancer (Stengel et al 2010;Tamura et al 2013;Li et al 2014;McCarroll et al 2015). Therefore, we performed Western blot to test the TUBB3 expression level and found it can be positively regulated by ART1, indicating that TUBB3 may participate in the ART1-enhanced VCR resistance of glioma cells.…”