A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K + Channel in Breast Cancer.

Autor:	Canella, Rita, Brugnoli, Federica, Gallo, Mariana, Keillor, Jeffrey W., Terrazzan, Anna, Ferrari, Elena, Grassilli, Silvia, Gates, Eric W. J., Volinia, Stefano, Bertagnolo, Valeria, Bianchi, Nicoletta, Bergamini, Carlo M.
Předmět:	BREAST tumor treatment TRANSGLUTAMINASES TREATMENT effectiveness HEALTH care teams CELL migration inhibition SURVIVAL analysis (Biometry) DESCRIPTIVE statistics RESEARCH funding CELL lines CYTOLOGY PHENOTYPES POTASSIUM antagonists
Zdroj:	Cancers; Jan2023, Vol. 15 Issue 1, p178, 19p
Abstrakt:	Simple Summary: This work intends to unravel one of the roles played by transglutaminase 2 within the cell. We highlighted its physical interaction with the voltage-dependent Kv10.1 K+ channel, an important target of therapies in breast cancer. The use of transglutaminase 2 inhibitors can selectively affect the membrane current of triple-negative cells in which this channel is functional. Since the multifunctionality of transglutaminase 2 (TG2) includes extra- and intracellular functions, we investigated the effects of intracellular administration of TG2 inhibitors in three breast cancer cell lines, MDA-MB-231, MDA-MB-436 and MDA-MB-468, which are representative of different triple-negative phenotypes, using a patch-clamp technique. The first cell line has a highly voltage-dependent a membrane current, which is low in the second and almost absent in the third one. While applying a voltage protocol to responsive single cells, injection of TG2 inhibitors triggered a significant decrease of the current in MDA-MB-231 that we attributed to voltage-dependent K+ channels using the specific inhibitors 4-aminopyridine and astemizole. Since the Kv10.1 channel plays a dominant role as a marker of cell migration and survival in breast cancer, we investigated its relationship with TG2 by immunoprecipitation. Our data reveal their physical interaction affects membrane currents in MDA-MB-231 but not in the less sensitive MDA-MB-436 cells. We further correlated the efficacy of TG2 inhibition with metabolic changes in the supernatants of treated cells, resulting in increased concentration of methyl- and dimethylamines, representing possible response markers. In conclusion, our findings highlight the interference of TG2 inhibitors with the Kv10.1 channel as a potential therapeutic tool depending on the specific features of cancer cells. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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