Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for ca...Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.展开更多
基金Beijing Municipal Natural Science Foundation(Grant No.7192100)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.
