Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press47710.17650/2313-805X-2022-9-4-61-70RESEARCH ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИAutophagy activation in breast cancer cells in vitro after the treatment with PI3K/AKT/mTOR inhibitorsАктивация аутофагии в клетках рака молочной железы in vitro после воздействия ингибиторами PI3K/AKT/mTORhttps://orcid.org/0000-0003-2675-089XGrigorevaD. D.ГригорьеваД. Д.
Russian Federation

Diana Dmitrievna Grigoreva

24 Kashirskoye Shosse, Moscow 115522

Диана Дмитриевна Григорьева

115522 Москва, Каширское шоссе, 24

grigodidmit@gmail.comhttps://orcid.org/0000-0003-3318-9391ZhidkovaE. M.ЖидковаЕ. М.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-6388-1624LylovaE. S.ЛыловаЕ. С.
Russian Federation

4 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7628-8616EnikeevA. D.ЕникеевА. Д.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-8599-6833KirsanovK. I.КирсановК. И.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

6 Miklukho-Maklaya St., Moscow 117198

115522 Москва, Каширское шоссе, 24

117198 Москва, ул. Миклухо-Маклая, 6

BelitskyG. A.БелицкийГ. А.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-9710-8178YakubovskayaM. G.ЯкубовскаяМ. Г.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-1967-9637LesovayaE. A.ЛесоваяЕ. А.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

9 Vysokovol’tnaya St., Ryazan 390026

115522 Москва, Каширское шоссе, 24

390026 Рязань, ул. Высоковольтная, 9

N.N. Blokhin National Medical Russian Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииPeoples’ Friendship University of RussiaФГАОУ ВО «Российский университет дружбы народов»I.P. Pavlov Ryazan State Medical University, Ministry of Health of RussiaФГБОУ ВО «Рязанский государственный медицинский университет им. И.П. Павлова» Минздрава России151220229417122022Copyright ©; 2022, Grigoreva D.D., Zhidkova E.M., Lylova E.S., Enikeev A.D., Kirsanov K.I., Belitsky G.A., Yakubovskaya M.G., Lesovaya E.A.Copyright ©; 2022, Григорьева Д.Д., Жидкова Е.М., Лылова Е.С., Еникеев А.Д., Кирсанов К.И., Белицкий Г.А., Якубовская М.Г., Лесовая Е.А.2022Grigoreva D.D., Zhidkova E.M., Lylova E.S., Enikeev A.D., Kirsanov K.I., Belitsky G.A., Yakubovskaya M.G., Lesovaya E.A.Григорьева Д.Д., Жидкова Е.М., Лылова Е.С., Еникеев А.Д., Кирсанов К.И., Белицкий Г.А., Якубовская М.Г., Лесовая Е.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/477

Introduction. Current chemotherapy of breast cancer has a wide range of disadvantages, in particular, the development of therapy-related infections and hormonal imbalance. Combination of main cytostatic with glucocorticoids allows to broaden its therapeutic interval and to decrease the total toxicity of the treatment. However, long-term treatment with glucocorticoids leads to the development of severe side effects via activation of multiple molecular mechanisms. Thus, glucocorticoids activate prosurvival mTOR-dependent autophagy. Therefore, the evaluation of PI3K (phosphoinositide 3-kinases) / Akt (protein kinase B) / mTOR (mammalian target of rapamycin) inhibitors as adjuvants for breast cancer therapy is important for optimization of treatment protocol.Aim. Analysis of the effects of PI3K/Akt/mTOR inhibitors, rapamycin, wortmannin and LY-294002 in combination with glucocorticoids in breast cancer cell lines of different subtypes.Materials and methods. We demonstrated the inhibition of PI3K/Akt/mTOR signaling and the autophagy induction after the treatment of breast cancer cells with rapamycin, wortmannin and LY-294002 by Western blotting analysis of Beclin-1, phospho-Beclin-1 (Ser93 and Ser30).Conclusion. PI3K/Akt/mTOR inhibitors in combination with Dexamethasone cooperatively inhibited mTOR signaling and activated autophagy in breast cancer cells in vitro.

Введение. Химиотерапия рака молочной железы имеет широкий спектр недостатков, в частности развитие сопутствующих инфекций и гормональных нарушений. Комбинация с синтетическими глюкокортикоидами позволяет расширить терапевтический интервал и снизить общую токсичность препаратов основной линии терапии. Однако длительное применение глюкокортикоидов способствует развитию ряда побочных эффектов, которые могут реализовываться за счет различных молекулярных механизмов. Так, глюкокортикоиды могут инициировать индукцию аутофагии, ведущую к выживанию опухолевых клеток. Запуск механизма аутофагии является mTOR-зависимым, в связи с чем актуальной является оценка возможности введения в качестве адъювантов в терапию рака молочной железы ингибиторов сигнального пути PI3K (фосфоинозитид-3‑киназа) / Akt (протеинкиназа B) / mTOR (мишень рапамицина млекопитающих).Цель работы – анализ действия ингибиторов PI3K / Akt / mTOR рапамицина, вортманнина и LY-294002 в комбинации с глюкокортикоидами на запуск аутофагии в клеточных линиях рака молочной железы различного гистогенеза.Материалы и методы. Методом Вестерн-блоттинга было показано, что рапамицин, вортманнин и LY-294002 ингибируют активность сигнального пути PI3K / Akt / mTOR и индуцируют аутофагию в клетках рака молочной железы, о чем судили по повышению уровня ключевого белка макроаутофагии, Beclin-1, и его фосфорилированных форм phospho-Beclin-1 по остаткам серина Ser93 и Ser30.Заключение. В ходе работы было показано, что ингибиторы сигнального пути PI3K / Akt / mTOR в комбинации с дексаметазоном кооперативно подавляют сигнальный путь mTOR и активируют аутофагию в клетках РМЖ in vitro.

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