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Ức chế PTK6 thúc đẩy quá trình apoptosis của tế bào ung thư vú Her2+ kháng Lapatinib bằng cách kích thích Bim
Tóm tắt
Protein tyrosine kinase 6 (PTK6) là một loại kinase tyrosine không thụ thể được biểu hiện mạnh ở bệnh ung thư vú dương tính với yếu tố tăng trưởng biểu bì người 2 (Her2+). Sự biểu hiện quá mức của PTK6 làm tăng khả năng sống sót phụ thuộc vào bám dính, sự tăng sinh và di cư của tế bào ung thư vú. Chúng tôi giả thuyết rằng việc ức chế PTK6 là một chiến lược hiệu quả để ức chế sự phát triển và sống sót của tế bào ung thư vú Her2+, bao gồm cả những tế bào tương đối kháng lại Lapatinib, một liệu pháp nhắm mục tiêu cho ung thư vú Her2+, dù là do tính kháng tự nhiên hay phát sinh sau khi tiếp xúc với thuốc liên tục. Để xác định tác động của việc ức chế PTK6 đối với các dòng tế bào ung thư vú Her2+ kháng Lapatinib (UACC893R1 và MDA-MB-453), chúng tôi đã sử dụng vector ribonucleic acid hình đuôi ngắn (shRNA) để giảm lượng PTK6. Chúng tôi đã xác định các tác động của việc giảm PTK6 đối với sự phát triển và sống sót trong ống nghiệm cũng như trong mô hình in vivo, cũng như các cơ chế chịu trách nhiệm cho các tác động này. Điều trị bằng Lapatinib trên các tế bào Her2+ “nhạy” gây ra cái chết tế bào qua quá trình apoptosis và tăng cường mức độ bản sao và protein của Bim, một thành viên của họ Bcl2 có tính pro-apoptotic. Ngược lại, điều trị các tế bào Her2+ tương đối “kháng” không thể kích thích Bim hoặc tăng cường mức độ của poly-ADP ribose polymerase (PARP) đã được cleaved. Việc giảm lượng PTK6 trong các tế bào “kháng” này làm tăng biểu hiện Bim, dẫn đến cái chết tế bào qua quá trình apoptosis. Giảm PTK6 cản trở sự phát triển của các tế bào này trong các mô hình nuôi cấy 3-D MatrigelTM in vitro, và cũng ức chế sự phát triển của các khối u chính Her2+. Biểu hiện Bim là rất quan trọng cho quá trình apoptosis do giảm PTK6, vì việc đồng biểu hiện shRNA Bim cứu sống các tế bào này khỏi cái chết do shRNA PTK6 gây ra. Sự điều hòa Bim bởi PTK6 không phải thông qua những thay đổi trong tín hiệu Erk/MAPK hoặc Akt, hai con đường được biết đến để điều chỉnh biểu hiện Bim. Thay vào đó, việc giảm PTK6 kích hoạt p38, và việc ức chế dược lý hoạt động của p38 ngăn chặn sự biểu hiện Bim do shRNA PTK6 gây ra và cứu tế bào khỏi quá trình apoptosis một phần. Việc giảm PTK6 gây ra quá trình apoptosis của các tế bào ung thư vú Her2+ kháng Lapatinib bằng cách tăng cường biểu hiện Bim thông qua việc kích hoạt p38. Bởi vì biểu hiện Bim là một biomarker quan trọng cho phản ứng với nhiều liệu pháp nhắm mục tiêu, việc ức chế PTK6 có thể cung cấp một hướng tiếp cận điều trị cho những bệnh nhân ung thư vú kháng liệu pháp nhắm mục tiêu Her2.
Từ khóa
#PTK6 #ung thư vú Her2+ #Lapatinib #apoptosis #BimTài liệu tham khảo
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