RESUMO
Bone metastasis in metastatic breast cancer commonly results in osteolytic lesions due to osteoclast activity, promoting bone destruction and tumor progression. The bioactive fungal isolates, 4-acetyl-antroquinonol B (4-AAQB) and erinacine A, have diverse pharmacological and biological activities. However, their effects on breast cancer bone metastasis treatment remain unclear. Our study aimed to examine the impact of 4-AAQB or erinacine A on breast cancer metastases in bone. The effects of 4-AAQB and erinacine A on breast cancer-induced osteoclastogenesis, breast cancer migration, production of prometastatic cytokine (TGF-ß) and marker (MMP-9), as well as potential MAPK signaling transductions were assessed. The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-ß and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.
Assuntos
Neoplasias da Mama , Metaloproteinase 9 da Matriz , Osteoclastos , Osteogênese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Animais , Fator de Crescimento Transformador beta/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Cicloexanonas , 4-Butirolactona/análogos & derivadosRESUMO
BACKGROUND: Extracellular acidification is a common feature of atherosclerotic lesions, and such an acidic microenvironment impedes ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and promotes atherogenesis. However, the underlying mechanism is still unclear. Acid-sensing ion channel 1 (ASIC1) is a critical H+ receptor, which is responsible for the perception and transduction of extracellular acidification signals. AIM: In this study, we explored whether or how ASIC1 influences extracellular acidification-induced ABCA1-mediated cholesterol efflux from macrophage-derived foam cells. METHODS: RAW 264.7 macrophages were cultured in an acidic medium (pH 6.5) to generate foam cells. Then the intracellular lipid deposition, cholesterol efflux, and ASIC1/calpain1/ABCA1 expressions were evaluated. RESULTS: We showed that extracellular acidification enhanced ASIC1 expression and translocation, promoted calpain1 expression and lipid accumulation, and decreased ABCA1 protein expression as well as ABCA1-mediated cholesterol efflux. Of note, inhibiting ASIC1 activation with amiloride or Psalmotoxin 1 (PcTx-1) not only lowered calpain1 protein level and lipid accumulation but also enhanced ABCA1 protein levels and ABCA1-mediated cholesterol efflux of macrophages under extracellular acidification conditions. Furthermore, similar results were observed in macrophages treated with calpain1 inhibitor PD150606. CONCLUSION: Extracellular acidification declines cholesterol efflux via activating ASIC1 to promote calpain1-mediated ABCA1 degradation. Thus, ASIC1 may be a novel therapeutic target for atherosclerosis.