Интерферирующая и антипролиферативная активности препаратов дцРНК в культурах опухолевых клеток человека различного происхождения тема диссертации и автореферата по ВАК РФ 03.01.04, кандидат биологических наук Акимов, Иван Алексеевич

• Акимов, Иван Алексеевич
• кандидат биологических наук
• 2012

Оглавление диссертации кандидат биологических наук Акимов, Иван Алексеевич

Список сокращений.

Введение.

Глава 1. Коррекция нарушений клеточного цикла с помощью siPHK (обзор литературы).

1.1. Введение: Регуляция клеточного цикла и ее нарушения как мишени для действия интерферирующих РНК.

1.2. Регуляция клеточного цикла.

1.2.1. Циклины и циклин-зависимые киназы.

1.2.2. Регуляция активности циклинов и циклин-зависимых киназ.

1.2.3. "Точки проверки" клеточного цикла.

1.3. Нарушения клеточного цикла и их причины.

1.3.1. Her2 (c-erb-B2/Neu).

1.3.2. Циклин В1.

1.3.3. Протеинкиназа С (РКС).

1.4. Клеточная дифференцировка.

1.4.1. Процессы клеточной дифференцировки.

1.4.2. Индукторы клеточной дифференцировки.

1.5. Ингибирование экспрессии генов с помощью siPHK.

1.5.1. РНК — интерференция.

1.5.2. Активация системы врожденного иммунитета под действием дцРНК.

1.5.3. Клинические испытания препаратов на основе siPHK.

1.5.4. Индукция клеточной дифференцировки с помощью siPHK.

Введение диссертации (часть автореферата) на тему «Интерферирующая и антипролиферативная активности препаратов дцРНК в культурах опухолевых клеток человека различного происхождения»

В настоящее время одной из первоочередных задач онкологии является повышение эффективности лечения опухолей, как путем разработки новых методов лечения, так и путем совершенствования традиционных терапевтических подходов. Хирургическое вмешательство, радиационное облучение и химиотерапия остаются классическими и наиболее распространенными методами лечения онкологических заболеваний. К сожалению, даже комплекс современных противоопухолевых мероприятий, часто не приводит к полной элиминации опухолевых клеток. Поэтому, несмотря на заметные достижения в области терапии онкологических заболеваний, увеличение эффективности лечения злокачественных опухолей и снижение токсичности химиотерапии путем создания лекарственных средств ген-направленного действия являются исключительно актуальными.

Важную роль в процессе злокачественной трансформации клеток играют гены, гиперэкспрессия которых приводит к неконтролируемой пролиферации (белки-регуляторы клеточного цикла) [ 1 ], блокированию апоптоза [ 2 ], нарушению процессов дифференцировки [3], повышению уровня генетической нестабильности [4], а также к усилению инвазивных свойств опухолевой клетки [5-9]. Наиболее часто, в опухолевых клетках наблюдается экспрессия мутантных форм или гиперэкспрессия нормальных клеточных генов, кодирующих рецепторы, транскрипционные факторы, тирозин-киназы и другие регуляторные белки.

Пути передачи сигналов в клетке включают множество дублирующих друг друга элементов, поэтому при подавлении экспрессии одного клеточного фактора, участвующего в передаче сигнала, возможна компенсация его функции путем активации альтернативного сигнального пути [9]. В связи с этим, поиск клеточных мишеней для направленного действия терапевтических агентов различной природы является актуальной задачей.

РНК-интерференция представляет собой процесс деградации мРНК-мишени, который индуцируется под действием двуцепочечных интерферирующих РНК длиной не менее 21-23 звеньев, гомологичных участку данной мРНК[10]. Этот процесс является эффективным способом регуляции экспрессии генов в эукариотических клетках, появившимся в процессе эволюции. Введение в клетку з1РНК определенной последовательности позволяет эффективно снизить уровень экспрессии генов, ассоциированных с заболеванием, до уровня, соответствующего уровню этой мРНК в нормальных клетках. На сегодняшний день интерферирующие РНК рассматриваются не только как перспективные лекарственные препараты, но и как эффективный инструмент для поиска молекулярных мишеней для действия лекарственных препаратов. Исследования показывают, что в каждом конкретном случае онкологического заболевания экспрессия большого числа генов, активирована или репрессирована по сравнению с нормальными родительскими клетками, и, исходя из этого, установление хронологии событий злокачественной трансформации является проблематичным [9]. Тем не менее, подавление экспрессии генов, которые кодируют белки, функционально расположенные на пересечении регуляторных каскадов или в начале этих каскадов, может привести к восстановлению контроля над делением клеток [11]. Взаимодействия различных генов, участвующих в процессах канцерогенеза интенсивно исследуются, но роль каждого гена в сложной системе с более чем одним генетическим нарушением требует углубленного изучения [12]. Нарушение регуляции генов, кодирующих компоненты передачи сигналов клеточного цикла рассматривается как ключевой фактор в развитии различных типов опухолей у человека[9, И, 12], тем не менее, терапевтическая значимость ингибирования таких генов в опухолях различного происхождения может существенно отличаться, поэтому для выбора наиболее эффективных мишеней требуется сравнение антипролиферативного действия игибиторов потенциальных мишеней на опухолевых клетках различного происхождения.

Цель и задачи исследования. Целью настоящей работы являлось создание специфических ингибиторов экспрессии генов, участвующих в регуляции клеточного цикла: Нег2 (с-егЬ-В2, пей), ССНВ1 (циклин В1) и РКС (протеинкиназа С), на основе дцРНК и исследование влияния этих ингибиторов на пролиферацию опухолевых клеток человека различного происхождения. В ходе исследования решались следующие задачи:

1. Исследовать эффективность и длительность ингибирующего действия малых интерферирующих РНК фРНК), направленных на мРНК генов Нег2, ССШ1 и РКС в опухолевых клетках человека различного происхождения.

2. Исследовать влияние длинных дцРНК, гомологичных мРНК генов с-Мус и ОРР на пролиферацию опухолевых клеток человека.

3. Исследовать изменение скорости пролиферации опухолевых клеток различного происхождения, подвергнутых действию з1РНК, направленных на мРНК генов Нег2, ССЫВ1 и РКС, после восстановления экспрессии генов-мишеней.

4. Исследовать влияние полученных з1РНК на изменение генной экспрессии в опухолевых клетках человека и их жизнеспособность.

Заключение диссертации по теме «Биохимия», Акимов, Иван Алексеевич

выводы

1. Разработаны siPHK (siHer, siCyc, siPKC), направленные к мРНК генов Her2, CCNB1 и РКС. Показано, что данные siPHK специфично ингибируют экспрессию генов-мишеней в клетках КВ-3-1, SK-N-MC, MCF-7 и HL-60: наибольшее снижение уровня мРНК-мишеней (до 10 - 20% от контроля) достигается через 3 суток после трансфекции, а исходный уровень экспрессии восстанавливается через 7 суток.

2. Показано, что ингибирование экспрессии генов Her2, CCNB1 и РКС с разной эффективностью замедляет деление клеток КВ-3-1, SK-N-MC, MCF-7, однако не влияет на пролиферацию клеток HL-60. Обнаружено, что наиболее выраженный антипролиферативный эффект наблюдается в клетках нейробластомы SK-N-MC под действием siCyc, а рост клеток MCF-7 наиболее эффективно тормозится под действием siPKC. Сравнение антипролиферативного действия siPHK, направленных к мРНК генов Her2, CCNB1 и РКС, на опухолевые клетки различного происхождения выполнено впервые.

3. Получены дцРНК, гомологичные мРНК генов с-Мус (dsMyc) и GFP (dsEGFP) длиной 473 и 448 п.н., соответственно. Показано, что препарат dsMyc, действующий как по механизму РНК-интерференции, так и через индукцию интерферонового ответа, снижает уровень экспрессии интерферон-чувствительного гена с-Мус более эффективно, чем препарат dsEGFP, действующий только по пути индукции интерферонового ответа. При этом оба препарата дцРНК со сравнимой эффективностью замедляют деление клеток КВ-3-1 и SK-N-MC.

4. Впервые изучено изменение скорости пролиферации исследованных клеточных линий после восстановления экспрессии генов Her2, CCNB1 и РКС. Показано, что скорость деления клеток КВ-3-1 восстанавливается после достижения исходного уровня экспрессии генов-мишеней, в то время как скорость деления SK-N-MC остается в 3 - 10 раз сниженной до 12 суток после воздействия siHer, siCyc и siPKC, а также длинных дцРНК.

5. Показано, что введение в клетки siPHK, направленных к мРНК генов Her2, CCNB1 и РКС не вызывает гибели клеток, а подавляет их деление, что подтверждается данными морфологического анализа. Напротив, доля мертвых клеток в популяции, трансфецированной длинной дцРНК значительно увеличивается, что связано с индукцией интерферонового ответа и вызванной им гибелью клеток.

6. С помощью полногеномного анализа транскриптома клеток SK-N-MC, трансфецированных siCyc и siPKC, обнаружено, что после восстановления экспрессии генов-мишеней, экспрессия определенных генов (EN02, AK3L1, ALDOC, TXNIP, В NIP, DDIT4 и др.) остается измененной, что может обуславливать длительное антипролиферативное действие исследуемых siPHK в этой клеточной линии.

3.10. Заключение

Нарушения регуляции клеточного цикла, являющиеся причиной развития опухолевых заболеваний, могут быть вызваны гиперэкспрессией или экспрессией химерных или мутантных вариантов регуляторных факторов, которые относятся к различным классам белков. Поэтому универсальным подходом для подавления их экспрессии является использование интерферирующих РНК, вызывающих деградацию мРНК-мишени по механизму РНК-интерференции. Такие интерферирующие РНК могут не только рассматриваться, как протопиты лекарственных препаратов нового поколения, но и использоваться для поиска новых молекулярных мишеней для препаратов другого типа действия. Ряд препаратов на основе з1РНК уже проходит клинические испытания, которые позволят выявить как терапевтический потенциал, так и их возможные побочные эффекты. Поскольку цепь передачи регуляторных сигналов в клетке носит каскадный характер и состоит из множества дублирующих друг друга путей, то важной задачей является поиск таких молекулярных мишеней, подавление экспрессии которых приводило бы к необратимым и некомпенсируемым последствиям для опухолевой клетки, к остановке ее деления.

В настоящей работе нами была предложениа и опробирована схема исследования влияния интерферирующих РНК на пролиферацию опухолевых клеток на примере вгРНК, гомологичных мРНК генов Нег2, ССЫВ1 и РКС, а также длинных дцРНК гомологичных мРНК генов с-Мус и ОРР. Обнаружено, что данные интерферирующие РНК с разной эффективностью замедляют деление опухолевых клеток различного происхождения, что указывает на необходимость идентификации индивидуальных молекулярных мишеней для терапии каждого типа опухолевого заболевания. Традиционной мишенью для ген-направленных препаратов, предназначенных для лечения опухоли молочной железы является ген Нег2, однако нами обнаружено, что значительно более эффективной мишенью для блокирования пролиферации клеток опухоли молочной железы МСР-7 является ген РКС. Наиболее эффективными мишенями для подавления роста нейробластомы БК-М-МС являются гены ССМВ1 и РКС, ингибирование экспрессии этих генов вызывает длительное снижение скорости пролиферации, которое сохраняется даже после восстановления исходного уровня экспрессии генов-мишеней. Данные гены могут рассматриваться как перспективные мишени для терапии нейробластом и рака малочной железы.

Полученные нами ингибиторы экспрессии генов Нег2, ССЫВ1 и РКС могут рассматриваться как прототипы лекарственных средств, для сдерживания роста опухолевых клеток, переживших химиотерапию, и, таким образом, могут стать одним из компонентов комплексной терапии при опухолевых заболеваниях и нейробластомах, в частности. Идентифицированные молекулярные мишени могут быть использованы также для поиска низкомолекулярных ингибиторов функций этих белков, для получения лекарственных средств нового поколения. Опробированная нами технологическая платформа может использоваться при скрининге молекулярных мишеней для противоопухолевых препаратов и может быть использована для расширенных исследований различной целевой направленности.

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