Gülşah EVYAPAN, Gülsevinç AY, Gamze CÖMERTPAY, H. Ümit LÜLEYAP

Tümörogenezisde endoplazmik retikulum stres cevabının rolü

Endoplazmik Retikulum (ER) ökaryotik hücrelerde bulunan, hücre içi kalsiyum homoastasizi, lipid sentezi, proteinlerin işlenmesi ve katlanmasından sorumlu olan bir organeldir. Hatalı katlanmış veya katlanmamış proteinlerin artması durumunda ortaya çıkan hücresel cevap endoplazmik retikulum stresi olarak adlandırılır. Değişen çevre koşullarına adaptasyonu sağlamak amacıyla evrimsel süreçte korunmuş bir mekanizma olan Katlanmamış Protein Cevabı (UPR) ile uyum sağlanmaya çalışılmaktadır. Ancak endoplazmik retikulum stresi ile başa çıkılamadığı durumlarda apopitoz tetiği çekilerek hücre ölümü meydana gelmektedir. Endoplazmik retikulum stresinin indüklediği apopitoz yolağında; CCAAT/enhance binding protein (C/EBP) homolog protein (CHOP), Mitojen tarafından aktive edilmiş protein kinaz (MAP kinaz) kaskadı, Bcl-2-ilişkili X protein (Bax/Bak), İnozitol Gerektiren Kinaz 1 (IRE1) ve kaspaz-12 gibi birçok molekül görev almaktadır. Endoplazmik retikulum stresinin kanser hücresi proliferasyonu ve sağkalımı üzerinde büyük bir etkisi vardır. Son yapılan araştırmalar endoplazmik retikulum stresi ve katlanmamış protein cevabının, kanserde önemli rol oynadığını göstermiştir. Nitekim, tümör hücrelerinin büyümesinde ve çevresel değişikliklere adaptasyonda rol oynayan katlanmamış protein cevabının, genellikle kanser hücrelerinin lehine çalışan bir süreç olarak kullanıldığı bulunmuştur. Endoplazmik retikulum stresinin tetiklediği katlanmamış protein cevabında tam olarak aydınlatılamamış bazı mekanizmaların varlığı, tedaviye giden süreci olumsuz yönde etkilemekte olduğundan bu mekanizmaların tam olarak aydınlatılmasıyla birlikte; hastalıkların daha iyi anlaşılması ve yeni tedavi stratejilerinin geliştirilmesinin de önü açılacaktır. Bu derlemede; kanser hücrelerinin endoplazmik retikulum stres cevabı ile proliferasyonlarını nasıl sürdürebildikleri, katlanmamış protein cevabı ekseninde ele alınacak ve bunun altında yatan moleküler mekanizmalara genel bir bakış yapılacaktır.

Anahtar Kelimeler:

Endoplazmik Retikulum, UPR, ER Stresi

Role of endoplasmic reticulum stress response in tumorogenesis

Endoplasmic Reticulum (ER) is an organelle found in eukaryotic cells, responsible for intracellular calcium homocysteine, lipid synthesis, processing and folding of proteins. The cellular response that occurs in the event of increased folded or unfolded proteins is called endoplasmic reticulum stress. In order to adapt to changing environmental conditions, it is attempted to adapt with the Unfolded Protein Response (UPR), a mechanism that has been preserved evolutionarily. However, in cases where endoplasmic reticulum stress can not be resolved, cell death is triggered via apoptosis. Several molecules such as C/EBP-Homologous Protein (CHOP), A mitogen-activated protein kinase (MAP K) cascade, BCL2 associated X protein (Bax / Bak), Inositol-requiring enzyme 1 (IRE1) and caspase-12 are involved in endoplasmic reticulum stress induces apoptosis pathway. Endoplasmic reticulum stress has a great influence on cancer cell proliferation and survival. Recent investigations have shown that endoplasmic reticulum stress and unfolded protein response play an important role in cancer. Indeed, the unfolded protein response, which plays a role in tumor cell growth and adaptation to environmental changes, has been found to be used as a process that is often favored by cancer cells. Since the existence of some mechanisms that are not fully understood in the unfolded protein response triggered by endoplasmic reticulum stress has affected negatively the process of treatment, fully clarification of these mechanisms leads to understanding of diseases and the development of new treatment strategies. In this review, how the cancer cells can survive via endoplasmic reticulum stress response and proliferation will be discussed in the unfolded protein response axis and an overview will be given to the underlying molecular mechanisms.

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