Publicação
The role of oncogenic KRAS in colorectal cancer: from subcellular localization upon autophagy induction to new therapeutic drugs
| Resumo: | Colorectal cancer (CRC) is the third most common cancer worldwide. KRAS mutations (KRAS ) are among the most frequent alterations in CRC supporting a role in colon carcinogenesis. MUT Our group showed that KRAS is involved in the regulation of autophagy in CRC. Indeed, we showed that under nutrient starvation conditions KRAS up-regulates autophagy in the colon model, which MUT is required for CRC cell survival. Autophagy is an important degradation pathway which regulates catabolic processes to sustain cellular metabolism and homeostasis. Differences in subcellular localization of RAS or interaction with other proteins may explain the complexity of their signaling outputs. Whether starvation induced-autophagy stimulus leads to relocalization of KRAS in CRC cells is still unknown. In this project, we aimed to understand if under autophagy induced conditions there were changes in wild-type and mutated KRAS subcellular localization and in interaction with partner proteins. Our results showed that KRAS co-localize with mitochondria and lysosomes regardless of autophagy induction and that KRAS may influence its mitochondria localization. MUT Moreover, our data suggest that Gal-3 and KRAS co-localize in colon cells and that autophagy does not interfere with the co-localization. We also observe that KRAS might interact with actin cytoskeleton, and that autophagy may influence actin remodeling possibly in a KRAS-dependent manner. KRAS mutations are a predictive biomarker of resistance in CRC, thus new therapeutic approaches are needed. MSG-111-cd3 is a phenoxazine derivative which had shown to induce cell death in yeast with the intervention of the vacuolar protease Pep4p, an orthologue of human Cathepsin-D (Cat-D). This project also aimed to study the effect of MSG-111-cd3 compound in CRC cells with different mutations. Our results showed that MSG-111-cd3 decrease cell viability more efficiently in CRC cells comparing with normal colon cells and that Cat-D seems to have a protective role in its effect. Overall, our data increased our understanding on KRAS localization and protein interaction in response to autophagy stimulus in CRC, which is crucial to understand KRAS signaling regulation. Furthermore, our data suggest that the new phenoxazine tested might be a promising candidate for CRC therapy. |
|---|---|
| Autores principais: | Almeida, Ana Filipa Martins de |
| Assunto: | Ciências Naturais::Ciências Biológicas |
| Ano: | 2018 |
| 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: | Colorectal cancer (CRC) is the third most common cancer worldwide. KRAS mutations (KRAS ) are among the most frequent alterations in CRC supporting a role in colon carcinogenesis. MUT Our group showed that KRAS is involved in the regulation of autophagy in CRC. Indeed, we showed that under nutrient starvation conditions KRAS up-regulates autophagy in the colon model, which MUT is required for CRC cell survival. Autophagy is an important degradation pathway which regulates catabolic processes to sustain cellular metabolism and homeostasis. Differences in subcellular localization of RAS or interaction with other proteins may explain the complexity of their signaling outputs. Whether starvation induced-autophagy stimulus leads to relocalization of KRAS in CRC cells is still unknown. In this project, we aimed to understand if under autophagy induced conditions there were changes in wild-type and mutated KRAS subcellular localization and in interaction with partner proteins. Our results showed that KRAS co-localize with mitochondria and lysosomes regardless of autophagy induction and that KRAS may influence its mitochondria localization. MUT Moreover, our data suggest that Gal-3 and KRAS co-localize in colon cells and that autophagy does not interfere with the co-localization. We also observe that KRAS might interact with actin cytoskeleton, and that autophagy may influence actin remodeling possibly in a KRAS-dependent manner. KRAS mutations are a predictive biomarker of resistance in CRC, thus new therapeutic approaches are needed. MSG-111-cd3 is a phenoxazine derivative which had shown to induce cell death in yeast with the intervention of the vacuolar protease Pep4p, an orthologue of human Cathepsin-D (Cat-D). This project also aimed to study the effect of MSG-111-cd3 compound in CRC cells with different mutations. Our results showed that MSG-111-cd3 decrease cell viability more efficiently in CRC cells comparing with normal colon cells and that Cat-D seems to have a protective role in its effect. Overall, our data increased our understanding on KRAS localization and protein interaction in response to autophagy stimulus in CRC, which is crucial to understand KRAS signaling regulation. Furthermore, our data suggest that the new phenoxazine tested might be a promising candidate for CRC therapy. |
|---|