RESUMO
BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) is associated with poor prognosis in malignant tumors. Sodium/glucose co-transporter 1 (SGLT1) is an active glucose transporter that is overexpressed in many cancers including prostate cancer. Previously, we found that EGFR interacts with and stabilizes SGLT1 in cancer cells. METHODS: In this study, we determined the micro-domain of EGFR that is required for its interaction with SGLT1 and the effects of activation/inactivation of EGFR on EGFR-SGLT1 interaction, measured the expression of EGFR and SGLT1 in prostate cancer tissues, and tested the effect of inhibition of SGLT1 on the sensitivity of prostate cancer cells to EGFR tyrosine inhibitors. RESULTS: We found that the autophosphorylation region (978-1210 amino acids) of EGFR was required for its sufficient interaction with SGLT1 and that this interaction was independent of EGFR's tyrosine kinase activity. Most importantly, the EGFR-SGLT1 interaction does not respond to EGFR tyrosine kinase modulators (EGF and tyrosine kinase inhibitors). EGFR and SGLT1 co-localized in prostate cancer tissues, and inhibition of SGLT1 by a SGLT1 inhibitor (Phlorizin) sensitized prostate cancer cells to EGFR inhibitors (Gefitinib and Erlotinib). CONCLUSION: These data suggest that EGFR in cancer cells can exist as either a tyrosine kinase modulator responsive status or an irresponsive status. SGLT1 is a protein involved in EGFR's functions that are irresponsive to EGFR tyrosine kinase inhibitors and, therefore, the EGFR-SGLT1 interaction might be a novel target for prostate cancer therapy.
Assuntos
Receptores ErbB/metabolismo , Próstata/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transportador 1 de Glucose-Sódio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Gefitinibe , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Purinas/farmacologia , Quinazolinas/farmacologiaRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.
Assuntos
Neoplasias Encefálicas , Indolamina-Pirrol 2,3,-Dioxigenase , Humanos , Animais , Camundongos , Triptofano , Quimera de Direcionamento de Proteólise , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
Glioblastoma (GBM) is the most common and aggressive form of malignant glioma in adults with a median overall survival (OS) time of 16-18 months and a median age of diagnosis at 64 years old. Recent work has suggested that depression and psychosocial distress are associated with worse outcomes in patients with GBM. We therefore hypothesized that the targeted neutralization of psychosocial distress with selective serotonin reuptake inhibitor (SSRI) antidepressant treatment would be associated with a longer OS among patients with GBM. To address this hypothesis, we retrospectively studied the association between adjuvant SSRI usage and OS in GBM patients treated by Northwestern Medicine-affiliated providers. The medical records of 497 GBM patients were analyzed after extraction from the Northwestern Medicine Enterprise Data Warehouse. Data were retrospectively studied using a multivariable Cox model with SSRI use defined as a time-dependent variable for estimating the association with OS. Of the 497 patients, 315 individuals died, while 182 were censored due to the loss of follow-up or were alive at the end of our study. Of the 497 patients, 151 had a recorded use of SSRI treatment during the disease course. Unexpectedly, SSRI usage was not associated with an OS effect in both naïve (HR = 0.81, 95% CI = 0.64-1.03) and adjusted time-dependent (HR = 1.26, 95% CI = 0.97-1.63) Cox models. Ultimately, we failed to find an association between SSRI treatment and an improved OS of patients with GBM. Additional work is necessary for understanding the potential therapeutic effects of SSRIs when combined with other treatment approaches, and immunotherapies in particular, for subjects with GBM.
RESUMO
Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.