Publicação
Molecular mechanisms underlying the anticancer activity of lactoferrin in highly metastatic cancer cell lines
| Resumo: | Cancer is currently one the most lethal disease worldwide and metastases remain the main cause of cancer-associated mortality, which reinforces the importance of developing more targeted and efficient cancer therapies. In this sense, lactoferrin (Lf) has emerged as a safe and effective agent in cancer therapy. Lf is a natural iron-binding protein derived from milk that is present in many tissues and biological fluids. Interestingly, it was found that Lf displays anticancer and anti-metastatic activities against several cancer cell lines. However, Lf cellular targets implicated in its mechanisms of action are poorly elucidated, which limits the usage of Lf in cancer therapy. Hence, unveiling the targets of Lf underlying its anticancer activity is of prime relevance and it will be explored in the current work. Recently, results of our group showed that bovine Lf (bLf) is preferentially cytotoxic to highly metastatic breast cancer cells through inhibition of the plasmalemmal proton pump V-ATPase, while exhibiting no effect on non-tumorigenic cells. In the present study, we aim to ascertain whether this same mechanism of action could explain the anticancer/anti-metastatic activity of bLf against other types of highly metastatic cancer cells. To this end, three highly metastatic cancer cell lines, reported to display V-ATPase at the plasma membrane, were used: PC-3, MG-63 and MDA-MB-231, prostate, osteosarcoma and breast cancer cell lines, respectively. Results showed that the susceptibility to bLf of PC-3 and MG- 63 cancer cell lines was similar to that of the breast cancer MDA-MB-231 regarding both inhibition of cell proliferation and induction of intracellular acidification. Moreover, we found that V-ATPase expression seemingly increased in the three cell lines in comparison to a non-tumorigenic cell line. These data encouraged us to implement several biochemical and analytical approaches, including flow cytometry, western blot, immunofluorescence and confocal microscopy in order to dissect the possible interplay between V-ATPase and bLf in these cell lines. Overall, the results herein obtained may be further explored to develop new cancer therapy strategies against highly metastatic cancers. |
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| Autores principais: | Guedes, Joana Catarina Pereira |
| Assunto: | Ciências Naturais::Ciências Biológicas |
| Ano: | 2017 |
| 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: | Cancer is currently one the most lethal disease worldwide and metastases remain the main cause of cancer-associated mortality, which reinforces the importance of developing more targeted and efficient cancer therapies. In this sense, lactoferrin (Lf) has emerged as a safe and effective agent in cancer therapy. Lf is a natural iron-binding protein derived from milk that is present in many tissues and biological fluids. Interestingly, it was found that Lf displays anticancer and anti-metastatic activities against several cancer cell lines. However, Lf cellular targets implicated in its mechanisms of action are poorly elucidated, which limits the usage of Lf in cancer therapy. Hence, unveiling the targets of Lf underlying its anticancer activity is of prime relevance and it will be explored in the current work. Recently, results of our group showed that bovine Lf (bLf) is preferentially cytotoxic to highly metastatic breast cancer cells through inhibition of the plasmalemmal proton pump V-ATPase, while exhibiting no effect on non-tumorigenic cells. In the present study, we aim to ascertain whether this same mechanism of action could explain the anticancer/anti-metastatic activity of bLf against other types of highly metastatic cancer cells. To this end, three highly metastatic cancer cell lines, reported to display V-ATPase at the plasma membrane, were used: PC-3, MG-63 and MDA-MB-231, prostate, osteosarcoma and breast cancer cell lines, respectively. Results showed that the susceptibility to bLf of PC-3 and MG- 63 cancer cell lines was similar to that of the breast cancer MDA-MB-231 regarding both inhibition of cell proliferation and induction of intracellular acidification. Moreover, we found that V-ATPase expression seemingly increased in the three cell lines in comparison to a non-tumorigenic cell line. These data encouraged us to implement several biochemical and analytical approaches, including flow cytometry, western blot, immunofluorescence and confocal microscopy in order to dissect the possible interplay between V-ATPase and bLf in these cell lines. Overall, the results herein obtained may be further explored to develop new cancer therapy strategies against highly metastatic cancers. |
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