Процесс апоптоза опухолевых клеток при воздействии орексинов

Орексины А и B — нейропептиды, синтезирующиеся небольшой популяцией нейронов латерального гипоталамуса. Их физиологическая функция заключается, главным образом, в регуляции цикла «сон-бодрствование», пищевого поведения, энергетического гомеостаза. Аксоны орек-син-содержащих нейронов проецируются во многие структуры головного и спинного мозга, что обеспечивает разнообразие их физиологических эффектов. Кроме того, компоненты орексинергической системы идентифицированы в различных периферических органах и тканях. Эффекты орексинов реализуются двумя рецепторами (OX1R и OX2R), связанными с G-белками (GPCRs). Классический путь передачи сигнала в нейрональных клетках через орексиновые рецепторы включает в себя увеличение концентрации внутриклеточного кальция в результате открытия мембранных каналов типа TRPC и каналов эндоплазматического ретикулума (ЭПР) типа IP3. Помимо этого, классического сигналинга орексиновых рецепторов, существует альтернативный путь, передача сигналов по которому приводит к апоптозу опухолевых клеток. Этот путь, вероятно, обусловлен структурной особенностью орексиновых рецепторов по сравнению с другими GPCRs — наличием иммунорецепторного мотива ингибирования на основе тирозина (ITIM). Такие мотивы не свойственны GPCRs, но являются отличительным признаком иммуноингибирующих рецепторов на лимфоидных и миелоидных клетках. ITIM рекрутирует либо белковые тирозинфосфатазы SHP1 и SHP2, либо инозитолфосфа-тазы SHIP1 и SHIP2 для опосредования негативной передачи сигналов. Дальнейший механизм так называемого орексин-индуцируемого апоптоза, по-видимому, включает в себя фосфорилирование p38/MAPK и высвобождение цитохрома с из митохондрий, с последующей активацией каспаз 3 и 7 и гибелью клеток. Следует подчеркнуть, что этот альтернативный путь представлен только в опухолевых клетках определенных типов. В настоящем обзоре обобщены имеющиеся данные об орексин-индуцированном апоптозе опухолевых клеток кишечника, поджелудочной железы, желудка, предстательной железы, эндометрия, надпочечников и глии, а также рассмотрены возможные механизмы его реализации.

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