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Aglycemia giữ phosphoryl hóa oxy hóa ty thể dưới điều kiện thiếu oxy ở tế bào HepG2
Tóm tắt
Sinh lý năng lượng tế bào ung thư, duy trì quá trình đường phân hiếu khí hỗn hợp (hiện tượng Warburg) và phosphoryl hóa oxy hóa (OXPHOS), vẫn chưa được làm sáng tỏ hoàn toàn. Sự ức chế OXPHOS phụ thuộc vào thiếu oxy quyết định quá trình đường phân hiếu khí. Để làm rõ thêm chi tiết, chúng tôi đã nghiên cứu sự thích ứng với thiếu oxy (lên đến 72 giờ với 5% oxy) của tế bào ung thư biểu mô gan HepG2. thành phần điều hòa chính, yếu tố gây thiếu oxy (HIF)-1α (HIF-1α) được ổn định ở 5 giờ trong môi trường 5% oxy cho cả ba chế độ nghiên cứu, tức là trong tế bào đường phân ở nồng độ glucose 5 mM hoặc 25 mM, hoặc trong tế bào aglycemic (Oxphos) khi glucose được thay thế bằng galactose. Tuy nhiên, sự ức chế hô hấp do HIF gây ra đã bị ngăn chặn trong tình trạng aglycemia, điều này có mối tương quan với tỷ lệ cao của pyruvate dehydrogenase (PDH) không được phosphoryl hóa ở 5% oxy. Phản ứng HIF bị chỉnh sửa trong tế bào Oxphos, được gọi là phản ứng phi chính thống, đối lập với sự ức chế hô hấp thông thường giảm xuống 45% hoặc 43%, được quan sát thấy trong tế bào đường phân thích nghi với thiếu oxy ở nồng độ glucose 5 mM hoặc 25 mM, tương ứng. Những tế bào đường phân thiếu oxy này thường có PDH được phosphoryl hóa cao và rất có thể đã sử dụng pyruvate thông qua phản ứng aminotransferase của glutaminolysis để cung cấp ít nhất là hô hấp bị ức chế. Ngoài ra, các tế bào đường phân có vẻ như là khá kháng với sự apoptosis do staurosporine gây ra, trong khi đó các tế bào HepG2 aglycemic (Oxphos) thể hiện độ nhạy cảm cao hơn nhiều. Chúng tôi kết luận rằng aglycemia điều chỉnh tín hiệu HIF thiếu oxy về một phản ứng phi chính thống mà không thể thực hiện phosphoryl hóa PDH hoàn chỉnh, cho phép đầu vào pyruvate cao cho OXPHOS từ quá trình đường phân tăng lên, điều này cùng với sự tiếp tục của glutaminolysis duy trì hô hấp gần như không thay đổi. Sự phục hồi OXPHOS tương tự có thể giải thích độ nhạy khác nhau của khối u với hóa trị liệu và các can thiệp dược lý khác.
Từ khóa
#ung thư #tế bào HepG2 #phosphoryl hóa oxy hóa #thiếu oxy #đường phân hiếu khí #yếu tố gây thiếu oxyTài liệu tham khảo
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