Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma.
Blood Cancer J
; 10(12): 125, 2020 12 14.
Article
em En
| MEDLINE
| ID: mdl-33318477
ABSTRACT
Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação para Baixo
/
Regulação Enzimológica da Expressão Gênica
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Regulação Neoplásica da Expressão Gênica
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Resistencia a Medicamentos Antineoplásicos
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Complexo de Endopeptidases do Proteassoma
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Inibidores de Proteassoma
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Mieloma Múltiplo
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Proteínas Musculares
Limite:
Humans
Idioma:
En
Revista:
Blood Cancer J
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos