RESUMO
Poly (ADP-ribose) polymerase 1 (PARP1) plays an essential role in DNA repair and is targeted by anticancer therapies using PARP inhibitors (PARPi) such as olaparib. PARPi treatment in prostate cancer (PC) is currently used as a monotherapy or in combination with standard therapies (hormonotherapy) in clinical trials for patients with DNA damage response mutation. Unfortunately, 20% of these patients did not respond to this new treatment. This resistance mechanism in PC is still not well understood. Here, we report that autophagy affects differently the response of PC cell lines to olaparib depending on its activation status. Pre-activation of autophagy before olaparib resulted in an increase of DNA repair activity by homologous recombination (HR) to repair double-strand breaks induced by olaparib and enhanced cell proliferation. When autophagy was activated after olaparib treatment, or completely inhibited, PC cells demonstrated an increased sensitivity to this PARPi. This autophagy-mediated resistance is, in part, regulated by the nuclear localization of sequestrosome 1 (SQSTM1/p62). Decrease of SQSTM1/p62 nuclear localization due to autophagy pre-activation leads to an increase of filamin A (FLNA) protein expression and BRCA1/Rad51 recruitment involved in the HR pathway. Our results reveal that autophagy basal levels may in part determine amenability to PARPi treatment.
Assuntos
Ftalazinas , Neoplasias da Próstata , Autofagia , Humanos , Masculino , Ftalazinas/farmacologia , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Proteína Sequestossoma-1RESUMO
Com o objetivo de testar e aprimorar o método de avaliação de trigo hexaplóide (Triticum aestivum L.), quanto a sua resposta a níveis tóxicos de alumínio com o uso de solução nutritiva, cinco genótipos de comportamento conhecido quanto a sua reação ao alumínio (Al+++), foram submetidos a solução nutritiva em três concentrações de Al+++ (4, 6 e l0ppm), em dois ensaios. Os resultados observados permitiram o ajuste do equipamento e aprimoramento do método de avaliação, assim como a definição da concentração ideal de Al+++ para seleção de genótipos tolerantes a este elemento.
Aiming to test and improve lhe method of evaluation of hexaploid wheat (Triticum aestivum L.) to aluminum toxic levels in nutritive solution. Five genotypes with known reaction to toxic aluminum (Al+++) were tested in nutritivo soluction in three different Al+++ concentrations (4, 6 e l0ppm), in two experiments. The results allowed the equipament ajustment, the choice of best evaluation method to select tolerant wheat genotypes to toxic Al+++ concentrations.
RESUMO
Se demuestra el incremento de los inhibidores trípticos en el suero de pacientes con pacreatitis aguda, con una técnica de laboratorio creada por nosotros y por inmunodifusión radial. Se estudia el significado de dicho aumento en la fisiopatología y pronóstico de esta enfermedad
Assuntos
Gravidez , Adulto , Humanos , Masculino , Feminino , Pancreatite/diagnóstico , Inibidores da Tripsina/sangue , Doença AgudaRESUMO
Se demuestra el incremento de los inhibidores trípticos en el suero de pacientes con T.B.C. en estado, de caquexia, con una técnica de laboratorio creada por nosotros y por inmunodifusión radial. Se constata que hay una relación directa entre la concentración en sangre de dichos inhibidores y el estado clínico del paciente. El incremento en el tubo digestivo de estos inhibidores explica la anorexia y posterior caquexia