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Perspectives
Novel Therapeutic Targets: The PERKs of Inhibiting the Integrated Stress Response
Jamie Blais and John C. Bell
volume 5 | issue 24
15 december 2006Pages: 2874 - 2877
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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 tumour 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 tumour 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 tumour survival. PERK can be activated by a number of distinct endoplasmic reticulum (ER) stresses as well as hypoxia and promotes a tumor microenvironment that favors the formation of functional microvessels and ultimately tumour growth. We hypothesize that ER stresse induced by sub-lethal doses of anticancer therapeutics could actually facilitate tumour 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.
Authors
Jamie Blais
Skirball Institute, NYU Medical Center; New York, NY USA
John C. Bell
Centre for Cancer Therapeutics, Ottawa Health Research Institute; Ottawa ON, Canada
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.