mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-TCA-2105mimmun-2105Research ArticleОБЗОРЫREVIEWSПроцесс апоптоза опухолевых клеток при воздействии орексиновTumor cell apoptosis mediated by the orexinsДятловаА. С.DiatlovaA. S.

Анастасия Сергеевна Дятлова — младший научный сотрудник отдела общей патологии и патофизиологии.

Санкт-Петербург

Anastasiia Sergeevna Diatlova, Junior Research Associate, Department of General Pathology and Pathological Physiology.

St. Petersburg

anst.diatlova@gmail.comНовиковаН. С.NovikovaN. S.

Наталия Сергеевна Новикова — кандидат биологических наук, старший научный сотрудник отдела общей патологии и патофизиологии.

Санкт-Петербург

Nataliia Sergeevna Novikova, PhD (Biology), Senior Research Associate, Department of General Pathology and Pathological Physiology.

novikiem@gmail.comДеревцоваК. З.DerevtsovaK. Z.

Кристина Зурабовна Деревцова — кандидат биологических наук, старший научный сотрудник отдела общей патологии и патофизиологии.

Санкт-Петербург

Kristina Zurabovna Derevtsova, PhD (Biology), Senior Research Associate, Department of General Pathology and Pathological Physiology.

kristina-shainidze@yandex.ruКорневаЕ. А.KornevaE. A.

Елена Андреевна Корнева — доктор медицинских наук, профессор, академик РАН, главный научный сотрудник отдела общей патологии и патофизиологии.

ФГБНУ Институт экспериментальной медицины

Elena Andreevna Korneva, PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Main Research Associate, Department of General Pathology and Pathological Physiology.

197376, St. Petersburg, Acad. Pavlov str., 12. Phone: 7 (812) 234-07-24

helen_korneva@mail.ruФГБНУ Институт экспериментальной медициныРоссияInstitute of Experimental MedicineRussian Federation202120062021233421438Copyright © Дятлова А.С., Новикова Н.С., Деревцова К.З., Корнева Е.А., 20212021Дятлова А.С., Новикова Н.С., Деревцова К.З., Корнева Е.А.Diatlova A.S., Novikova N.S., Derevtsova K.Z., Korneva E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2105

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.

Orexins A and B are neuropeptides synthesized by a population of lateral hypothalamic neurons. Orexin’s physiological function consists mainly in regulating the sleep-wake cycle, eating behavior, and energy homeostasis. Axons of orexin-containing neurons are projected onto many structures of brain and spinal cord, thus providing a variety of their physiological effects. Moreover, the components of the orexinergic system are identified in various peripheral organs and tissues. The effects of orexins are mediated via two receptors (OX1R and OX2R) coupled with G-proteins (GPCRs). The classical signal transmission pathway through orexin receptors in neuronal cells includes an increase of the intracellular calcium as a result of the opening of TRPC membrane channels and IP3 endoplasmic reticulum (ER) channels. In addition to the classic orexin receptors signaling, there is an alternative pathway. Signal transmission through the alternative pathway leads to apoptosis of tumor cells. This pathway is probably due to the structural feature of orexin receptors compared to other GPCRs — the presence of a tyrosine-based immunoreceptor inhibition motif (ITIM). Such motifs are not limited to GPCRs, but are a hallmark of immuno-inhibiting receptors on lymphoid and myeloid cells. ITIM recruits either SHP1 and SHP2 protein tyrosine phosphatases or SHIP1 and SHIP2 inositol phosphatases, to mediate negative signal transduction. A further mechanism of the so-called orexin-induced apoptosis seems to include the p38/MAPK phosphorylation and the cytochrome c releasing from mitochondria, followed by activation of caspases 3 and 7 and cell death. It should be emphasized that this alternative pathway is present only in certain types of tumor cells. This review summarizes the available data on orexin-induced apoptosis of tumor cells from intestines, pancreas, stomach, prostate, endometrium, adrenal glands and glia, and also considers possible mechanisms for its implementation.

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The authors declare that there are no conflicts of interest present.