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Cisplatin-induced activation of TGF-β signaling contributes to drug resistance

SAYAKA IMATSUJI1,#, YUKIKO UJIE1,#, HIROYUKI ODAKE1, MASAYA IMOTO1,2, SUSUMU ITOH3, ETSU TASHIRO1,3,*

1 Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, 223-8522, Japan
2 Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan
3 Laboratory of Biochemistry, Showa Pharmaceutical University, Tokyo, 194-8543, Japan

* Corresponding Author: ETSU TASHIRO. Email: email

(This article belongs to this Special Issue: Approach from Chemical Biology for Cancer Research)

Oncology Research 2024, 32(1), 139-150. https://doi.org/10.32604/or.2023.030190

Abstract

Growing evidence suggests an association between epithelial-mesenchymal transition (EMT), a hallmark of tumor malignancy, and chemoresistance to a number of anti-cancer drugs. However, the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear. To address this issue, we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts. In these clones, the epithelial marker E-cadherin was downregulated, whereas the mesenchymal marker N-cadherin was upregulated. Moreover, the expression of EMT-related transcription factors, including Slug, was elevated. On the other hand, the upregulation of other mesenchymal marker Vimentin was weak, suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones. These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β (TGF-β) receptor kinase inhibitors, indicating that TGF-β signaling is involved in cisplatin-induced the mesenchymal-like phenotypic changes. Moreover, cisplatin was observed to enhance the secretion of TGF-β into the culture media without influencing TGF-β gene transcription. These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-β secretion, ultimately resulting in drug resistance.

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Cite This Article

IMATSUJI, S., UJIE, Y., ODAKE, H., IMOTO, M., ITOH, S. et al. (2024). Cisplatin-induced activation of TGF-β signaling contributes to drug resistance. Oncology Research, 32(1), 139–150.



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