Estudo da proteína de choque térmico GRP78 para o desenvolvimento de um sistema de receptor-ligante para o câncer de próstata / Use of the heat-shock protein GRP78 for the development of a receptor-ligand system in prostate cancer

AUTOR(ES)
DATA DE PUBLICAÇÃO

2003

RESUMO

Introduction: Despite the advances in diagnosis and treatment, advanced prostate cancer remains a lethal condition. Improved methods of therapy are needed to reduce the morbidity and mortality rates associated with this disease. The Glucose-regulated protein-78 (GRP78), a stress-responsive heat-shock protein involved in antigen presentation, was recently described as a possible molecular marker for prostate cancer. Moreover, immune response against this protein was shown to have correlation with the development of androgen-independent prostate cancer and shorter overall survival. Objectives: We hipothesized that GRP78 could be used as a molecular marker for prostate cancer in the development of a receptor-ligand system, by using phage display technology. Patients and methods: We initially cloned two GRP78-targeting peptides (WIFPWIQL and WDLAWMFRLPVG) into a fUSE5-based phage. We then tested binding capacity of the phage to GRP78 in vitro, to GRP78 expressed in intact prostate cancer cell membranes, to a prostate cancer xenograft and to human bone metastases. Results: We showed that both phage created bound specifically to GRP78 in vitro, in comparison to related (Heat-shock proteins 70 and 90) and unrelated control proteins (bovine serum albumin). Next, we showed that these phage bound at least 30 times more to prostate cancer cells than the control phage, and were also internalized into these cells. Both GRP78-binding phage showed a strong homing in vivo to a human prostate cancer xenograft in a mouse model. Finally, we showed that both phage bound specifically to GRP78 expressed in human prostate cancer bone metastases. Conclusions: Both phage are capable of binding specifically to GRP78 in vitro, in the context of intact prostate cancer cells and in vivo. The strategy and the ligand-receptor system we have defined in this study may have relevant implications in the development of targeted therapies for the treatment of prostate cancer.

ASSUNTO(S)

immunohistochemistry/methods enzyme-linked immunosorbent assay/methods neoplasm metastasis sítios de ligação (microbiologia)/genética bacteriophages/growth &development metástase neoplásica biological markers/analysis mice nude gene expression/genetics prostatic neoplasms/genetics camundongos nus elisa/métodos neoplasias prostáticas/diagnóstico neoplasias prostáticas/genética bacteriophages/genetics attachment sites microbiological/genetics imunohistoquímica/métodos marcadores biológicos de tumor/análise bacteriófagos/genética ligantes neoplasm staging estadiamento de neoplasias bacteriófagos/crescimento &desenvolvimento ligands expressão gênica/genética prostatic neoplasms/diagnosis

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