Publicação
Loss of proteostasis in cancer and its relation with acquired resistance to endocrine therapy
| Resumo: | Cancer has enormous costs for society with breast and prostate cancers accounting for the first and fifth cause of death among cancer patients. About 50% of the initially responsive breast cancers and almost all prostate cancers develop resistance to endocrine therapy, progressing towards a more aggressive, metastatic, and incurable disease. Thus, discovery of novel biomarkers to monitor patients’ response as well as new drug targets to surpass resistance are urgently needed. Cancer cells thrive under physiologic conditions that induce oxidative and proteotoxic stress, leading to protein misfolding and aggregation, which results in loss of proteostasis. To resolve proteotoxic stress, cells activate protein quality control mechanisms, being the Unfolded Protein Response (UPR) one of them. While it has been shown that specific UPR branches are activated in endocrine resistant breast and prostate cancer cells, there is nearly no knowledge about the specific proteins that aggregate, the biological processes they regulate, how protein aggregates affect cell survival and how this influences the acquisition of a resistant phenotype. Therefore, we proposed to identify and characterize the changes in signalling pathways regulating the proteostasis network leading to protein aggregation in endocrine-responsive vs resistant breast and prostate cancer cells. We characterized the aggregated proteome of breast cancer cell lines and identified a novel protein involved in acquired antiestrogen resistance – RNA-Splicing Ligase RtcB homolog (RTCB). We also explored the predictive value of RTCB and the endoplasmic reticulum chaperone BiP (BiP) in luminal breast cancer and evaluated the effect of antiestrogen therapy and metastasis on RTCB aggregation, aggresome formation and BiP expression. Our results show that RTCB aggregation status could be used as a potential predictive tool to evaluate the response of breast cancer patients to antiestrogen therapy. In addition, by combining three different strategies (analysis of publicly available datasets; systematic review and meta-analysis of immunohistochemistry (IHC) detection of BiP in human breast cancers; and IHC detection of BiP in our own cohorts) we confirmed the potential of BiP as an indicator of poor prognosis for breast cancer patients. We showed that castration resistant prostate cancer (CRPC) cells protect their proteome from flutamide-induced toxic aggresome accumulation through the activation of two distinct stress responses that work in concert. The antioxidative stress response is firstly activated to cope with reactive oxygen species (ROS) production. Secondly, UPR activation results in a transient inhibition of protein translation to avoid protein aggregation/ aggresome formation. We also identified Eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) as a novel protein involved in acquired antiandrogen resistance in CRPC cells. Thus, with this work, we propose for the first time, that protein aggregation patterns could be indicative of the capacity of cells to maintain a healthy proteome in response to treatment, which provides a new perspective of proteostasis, where protein aggregation can be used to identify novel biomarkers and drug targets and should be considered as a novel approach to understand mechanisms of disease. |
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| Autores principais: | Direito, Inês Gomes |
| Assunto: | Proteostasis Breast cancer Prostate cancer Endocrine therapy resistance Unfolded protein response (UPR) Protein aggregation |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | Cancer has enormous costs for society with breast and prostate cancers accounting for the first and fifth cause of death among cancer patients. About 50% of the initially responsive breast cancers and almost all prostate cancers develop resistance to endocrine therapy, progressing towards a more aggressive, metastatic, and incurable disease. Thus, discovery of novel biomarkers to monitor patients’ response as well as new drug targets to surpass resistance are urgently needed. Cancer cells thrive under physiologic conditions that induce oxidative and proteotoxic stress, leading to protein misfolding and aggregation, which results in loss of proteostasis. To resolve proteotoxic stress, cells activate protein quality control mechanisms, being the Unfolded Protein Response (UPR) one of them. While it has been shown that specific UPR branches are activated in endocrine resistant breast and prostate cancer cells, there is nearly no knowledge about the specific proteins that aggregate, the biological processes they regulate, how protein aggregates affect cell survival and how this influences the acquisition of a resistant phenotype. Therefore, we proposed to identify and characterize the changes in signalling pathways regulating the proteostasis network leading to protein aggregation in endocrine-responsive vs resistant breast and prostate cancer cells. We characterized the aggregated proteome of breast cancer cell lines and identified a novel protein involved in acquired antiestrogen resistance – RNA-Splicing Ligase RtcB homolog (RTCB). We also explored the predictive value of RTCB and the endoplasmic reticulum chaperone BiP (BiP) in luminal breast cancer and evaluated the effect of antiestrogen therapy and metastasis on RTCB aggregation, aggresome formation and BiP expression. Our results show that RTCB aggregation status could be used as a potential predictive tool to evaluate the response of breast cancer patients to antiestrogen therapy. In addition, by combining three different strategies (analysis of publicly available datasets; systematic review and meta-analysis of immunohistochemistry (IHC) detection of BiP in human breast cancers; and IHC detection of BiP in our own cohorts) we confirmed the potential of BiP as an indicator of poor prognosis for breast cancer patients. We showed that castration resistant prostate cancer (CRPC) cells protect their proteome from flutamide-induced toxic aggresome accumulation through the activation of two distinct stress responses that work in concert. The antioxidative stress response is firstly activated to cope with reactive oxygen species (ROS) production. Secondly, UPR activation results in a transient inhibition of protein translation to avoid protein aggregation/ aggresome formation. We also identified Eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) as a novel protein involved in acquired antiandrogen resistance in CRPC cells. Thus, with this work, we propose for the first time, that protein aggregation patterns could be indicative of the capacity of cells to maintain a healthy proteome in response to treatment, which provides a new perspective of proteostasis, where protein aggregation can be used to identify novel biomarkers and drug targets and should be considered as a novel approach to understand mechanisms of disease. |
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