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.

A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K+ Channel in Breast Cancer / 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. - In: CANCERS. - ISSN 2072-6694. - 15:1(2022), p. 178. [10.3390/cancers15010178]

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

Gallo, Mariana;Ferrari, Elena;
2022-01-01

Abstract

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.
2022
A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K+ Channel in Breast Cancer / 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. - In: CANCERS. - ISSN 2072-6694. - 15:1(2022), p. 178. [10.3390/cancers15010178]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2938240
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 1
social impact