Blais Jaime, Bell John C
Skirball Institute, New York University Medical Centre, New York, New York, USA.
Cell Cycle. 2006 Dec;5(24):2874-7. doi: 10.4161/cc.5.24.3597. Epub 2006 Dec 13.
Oxygen supports the life of all aerobic organisms and virtually every cell type is capable of sensing decreased tissue oxygenation or hypoxia. Hypoxic microenvironments are known to exist within developing solid tumors as a result of insufficient vascular delivery of oxygen, which can limit the efficient growth and spread of the malignancy. On the other hand, clinical and experimental evidence has demonstrated that reduction in tumor blood flow can diminish the efficacy of standard anticancer therapeutics including radiotherapy and chemotherapy. Indeed, low oxygenation can accelerate malignant progression and metastasis resulting in poorer prognosis irrespective of the chosen treatment regiment. We and others have shown that tumor cells cultured under hypoxic conditions and cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). One of the key master switches in the ISR is the dynamically regulated protein kinase known as PERK. Tumors that lack PERK activity are small and compromised in their ability to translate mRNAs involved in angiogenesis and tumor survival. PERK can be activated by a number of distinct endoplasmic reticulum (ER) stress as well as hypoxia and promotes a tumor microenvironment that favors the formation of functional microvessels and ultimately tumor growth. We hypothesize that ER stress induced by sub-lethal doses of anti-cancer therapeutics could actually facilitate tumor progression by activation of the ISR. We propose that inhibitors of PERK may synergize with a variety of cancer therapeutics that directly or indirectly induce the ISR.
氧气维持着所有需氧生物的生命，几乎每种细胞类型都能够感知组织氧合减少或缺氧情况。由于氧气的血管输送不足，已知在实体瘤发生过程中存在缺氧微环境，这会限制恶性肿瘤的有效生长和扩散。另一方面，临床和实验证据表明，肿瘤血流减少会降低包括放疗和化疗在内的标准抗癌疗法的疗效。事实上，无论选择何种治疗方案，低氧合都会加速恶性进展和转移，导致预后较差。我们和其他人已经表明，在缺氧条件下培养的肿瘤细胞以及肿瘤缺氧区域的细胞会激活一种称为综合应激反应（ISR）的翻译控制程序。ISR中的一个关键主开关是一种动态调节的蛋白激酶，称为PERK。缺乏PERK活性的肿瘤体积较小，并且在翻译参与血管生成和肿瘤存活的mRNA方面能力受损。PERK可被多种不同的内质网（ER）应激以及缺氧激活，并促进有利于功能性微血管形成并最终促进肿瘤生长的肿瘤微环境。我们假设，亚致死剂量的抗癌疗法诱导的内质网应激实际上可能通过激活ISR促进肿瘤进展。我们提出，PERK抑制剂可能与直接或间接诱导ISR的多种癌症疗法协同作用。
