The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies

Abstract

In recent years considerable progress has been made in identifying the impact of mRNA translation in tumour progression. Cancer cells hijack the pre-existing translation machinery to thrive under the adverse conditions originating from intrinsic oncogenic programs, that increase their energetic demand, and from the hostile microenvironment. A key translation program frequently dysregulated in cancer is the Integrated Stress Response, that reprograms translation by attenuating global protein synthesis to decrease metabolic demand while increasing translation of specific mRNAs that support survival, migration, immune escape. In this review we provide an overview of the Integrated Stress Response, emphasise its dual role during tumorigenesis and cancer progression, and highlight the therapeutic strategies available to target it.

Keywords: Adaptive/maladaptive; Cancer; ISR activators; ISR inhibitors; Integrated Stress Response; Translation reprogramming; eIF2α.