Kanser ve Endoplazmik Retikulum Stres İndüklü Apoptoz Arasındaki İlişki

Öz

Endoplazmik retikulum (ER); protein sentezi, katlanması ve lipid biyosentezi gibi kritik hücresel süreçlerde merkezi bir rol oynar. ER stres, yanlış katlanmış proteinlerin birikmesiyle tetiklenir ve hücrenin hayatta kalmasını sağlamak için Unfolded Protein Response (UPR) yolaklarını aktive eder. UPR; PRKR benzeri ER Kinaz (PERK), İnozitol Gerektiren Enzim 1 (IRE1) ve Aktive edici transkripsiyon faktör 6 (ATF6) gibi sensörler aracılığıyla ER homeostazını restore etmeye çalışır. Ancak, uzun süreli veya şiddetli ER stres, apoptozu tetikleyerek hücre ölümüne yol açabilir. Kanser hücrelerinde, tümör mikroçevresindeki hipoksi, besin yetersizliği ve oksidatif stres gibi faktörler kronik ER strese neden olur. Bu koşullar altında, UPR'nin aktivasyonu kanser hücrelerinin hayatta kalmasını desteklerken, aşırı ER stres apoptozu indükleyebilir. ER stres ve UPR'nin kanser progresyonundaki rolü, hem tümör büyümesini destekleyici hem de apoptozu tetikleyici etkileri nedeniyle karmaşıktır. Örneğin, IRE1α- X-Box Bağlayıcı Protein 1 (XBP1) ve PERK- Ökaryotik Translasyon Başlatma Faktörü 2α (eIF2α)- Aktive edici transkripsiyon faktör 4 (ATF4) yolakları, kanser hücrelerinde hayatta kalma ve kemorezistansı artırabilirken, C/EBP Homolog Protein (CHOP) ve C-Jun N-Terminal Kinaz (JNK) gibi pro-apoptotik sinyaller hücre ölümünü tetikleyebilir. Bu dengenin anlaşılması, kanser tedavisi için yeni hedefler sunmaktadır. Proteazom inhibitörleri ve ER stresini artıran diğer ajanlar, kanser hücrelerinde apoptozu indükleyerek terapötik potansiyele sahiptir. Bu derleme, ER stres, UPR ve ER strese bağlı apoptozun moleküler mekanizmalarını inceleyerek, kanser hücrelerinde bu süreçlerin nasıl manipüle edilebileceğini ve yeni tedavi stratejilerinin nasıl geliştirilebileceğini tartışmaktadır. ER stres yolaklarının hedeflenmesi, özellikle kemorezistan tümörler için umut verici bir yaklaşım olabilir.

Anahtar Kelimeler

• Endoplazmik retikulum stresi
• katlanmamış protein yanıtı
• apoptoz
• hücrenin hayatta kalması
• kanser

THE RELATIONSHIP BETWEEN CANCER AND ENDOPLASMIC RETICULUM STRESS-INDUCED APOPTOSIS

Öz

The endoplasmic reticulum (ER) plays a central role in critical cellular processes such as protein synthesis, folding, and lipid biosynthesis. ER stress is triggered by the accumulation of misfolded proteins and activates the Unfolded Protein Response (UPR) pathways to ensure cell survival. The UPR attempts to restore ER homeostasis through sensors such as PKR-like ER Kinase (PERK), Inositol-Requiring Enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6). However, prolonged or severe ER stress can lead to cell death by triggering apoptosis. In cancer cells, factors such as hypoxia, nutrient deprivation, and oxidative stress in the tumor microenvironment contribute to chronic ER stress. Under these conditions, activation of the UPR supports cancer cell survival, while excessive ER stress can induce apoptosis. The role of ER stress and the UPR in cancer progression is complex due to their dual effects in both promoting tumor growth and triggering apoptosis. For instance, the IRE1α-X-Box Binding Protein 1 (XBP1) and PERK-Eukaryotic Translation Initiation Factor 2α (eIF2α)- Activating Transcription Factor 4 (ATF4) pathways can enhance survival and chemoresistance in cancer cells, while pro-apoptotic signals such as C/EBP Homologous Protein (CHOP) and c-Jun N-Terminal Kinase (JNK) can trigger cell death. Understanding this balance offers new targets for cancer therapy. Proteasome inhibitors and other agents that increase ER stress have therapeutic potential by inducing apoptosis in cancer cells. This review examines the molecular mechanisms of ER stress, the UPR, and ER stress-induced apoptosis, discussing how these processes can be manipulated in cancer cells and how new treatment strategies can be developed. Targeting ER stress pathways may represent a promising approach, particularly for chemoresistant tumors.

Anahtar Kelimeler

• Endoplasmic reticulum stress
• unfolded protein response
• apoptosis
• cell survival
• cancer

Kaynakça

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