Publicação
A multidisciplinary approach to unveil the mechanisms underlying lactoferrin antifungal and anticancer activities
| Resumo: | Lactoferrin (Lf) is a versatile iron-binding protein abundant in milk and colostrum that exhibits several interesting biological activities, from which its antifungal and anticancer activities are particularly promising. Since the molecular basis underlying these activities are still not fully elucidated, herein we aimed at achieving a more comprehensive knowledge on this subject, envisioning an improved application of Lf against fungal infections and cancer. To this end, a multidisciplinary approach using yeast and cancer cells as cellular models was carried out. Lf has been shown to exert a powerful antifungal activity against several species of yeasts and filamentous fungi. Increasing research has been focused on understanding the mechanisms underlying this activity towards the development of novel Lf-based antifungal strategies. For instance, Lf was demonstrated to induce an apoptotic-like regulated cell death process in both Saccharomyces cerevisiae and Candida albicans. To get further insights on this process, we sought to investigate whether autophagy, a degradative process by which cells deliver cellular components to the vacuole, plays a role in Lf-induced yeast cell death. Using pharmacological and genetic approaches, we demonstrate that Lf antifungal activity depends on autophagy activation. Lf has also been demonstrated to display a strong anticancer activity against several cancer types, and some underlying mechanisms have been proposed, including cell cycle arrest, apoptosis induction and metastasis/invasion inhibition. Given that Lf has high affinity to iron and iron metabolism is critical for cancer cells, we explored for the first time the iron-cancer-Lf axis. For that purpose, we assessed the effect of Lf on the expression and localization of iron metabolism related proteins in highly metastatic breast cancer and non-cancer cells. Moreover, their expression, as well as Lf antiproliferative capacity, were evaluated upon iron chelation and supplementation. Our results demonstrate that Lf modulates the expression and localization of some iron metabolism-related proteins, induces severe changes in cytoskeleton organization, and that iron chelation and supplementation change the effect of Lf in a breast cancer cell line. Overall, though further research is needed, our results point to the combination of Lf with autophagy inducers as a promising antifungal strategy, as well as the perturbation of iron homeostasis as a Lf mechanism against cancer cells. |
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| Autores principais: | Madaleno, Rita de Sousa |
| Assunto: | Anticancer Antifungal Autophagy Iron Lactoferrin Anticancerígeno Antifúngico Autofagia Lactoferrina Ferro |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Lactoferrin (Lf) is a versatile iron-binding protein abundant in milk and colostrum that exhibits several interesting biological activities, from which its antifungal and anticancer activities are particularly promising. Since the molecular basis underlying these activities are still not fully elucidated, herein we aimed at achieving a more comprehensive knowledge on this subject, envisioning an improved application of Lf against fungal infections and cancer. To this end, a multidisciplinary approach using yeast and cancer cells as cellular models was carried out. Lf has been shown to exert a powerful antifungal activity against several species of yeasts and filamentous fungi. Increasing research has been focused on understanding the mechanisms underlying this activity towards the development of novel Lf-based antifungal strategies. For instance, Lf was demonstrated to induce an apoptotic-like regulated cell death process in both Saccharomyces cerevisiae and Candida albicans. To get further insights on this process, we sought to investigate whether autophagy, a degradative process by which cells deliver cellular components to the vacuole, plays a role in Lf-induced yeast cell death. Using pharmacological and genetic approaches, we demonstrate that Lf antifungal activity depends on autophagy activation. Lf has also been demonstrated to display a strong anticancer activity against several cancer types, and some underlying mechanisms have been proposed, including cell cycle arrest, apoptosis induction and metastasis/invasion inhibition. Given that Lf has high affinity to iron and iron metabolism is critical for cancer cells, we explored for the first time the iron-cancer-Lf axis. For that purpose, we assessed the effect of Lf on the expression and localization of iron metabolism related proteins in highly metastatic breast cancer and non-cancer cells. Moreover, their expression, as well as Lf antiproliferative capacity, were evaluated upon iron chelation and supplementation. Our results demonstrate that Lf modulates the expression and localization of some iron metabolism-related proteins, induces severe changes in cytoskeleton organization, and that iron chelation and supplementation change the effect of Lf in a breast cancer cell line. Overall, though further research is needed, our results point to the combination of Lf with autophagy inducers as a promising antifungal strategy, as well as the perturbation of iron homeostasis as a Lf mechanism against cancer cells. |
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