Perk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress

Abstract

MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.The presence of hypoxic cells in solid tumors is well documented, and clinical and experimental evidence suggests that the hypoxic microenvironment of a tumor promotes a more aggressive phenotype by selecting for the clonal expansion of apoptotically insensitive cells (28). Growing tumors are often exposed to heterogeneous environments with regions of solid tumors containing microenvironmental niches deficient of critical metabolites, such as oxygen and glucose (11). Indeed, low oxygenation can accelerate malignant progression and metastasis, resulting in a poorer prognosis irrespective of the chosen treatment regimen (38). The ability of tumor cells to survive and adapt to hypoxic microenvionments can be attributed to the regulation of several key mechanisms, including the loss of pathways that can induce cell death (28), the stimulation of angiogenesis to increase tumor oxygenation (87), and the capability to strictly regulate energy homeostasis (37). Energy conservation is crucial to cellular survival, as ATP production is diminished by the lack of oxidative phosphorylation. Thus, hypoxic stress results in a rapid metabolic shift that favors anaerobic glycolysis and the inhibition of high-energy-consuming processes, including protein translation (75).The control of mRNA translation is emerging as an important cellular response to stress that can assert a significant influence on individual gene expression (9,22,31,48,50,65,79). Hypoxia results in a rapid and reversible inhibition in global protein synthesis to help alleviate energy demands when oxygen and ATP levels are low; however, the exact mechanisms controlling translational regulation are not fully understood. While early responses to hypoxia involve the activation of Perk and transient phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2␣) (7, 9, 51), translational inhibition appears to occur in distinct phases and to involve multiple pathways (16,50,59). Exposure to hypoxia activates the endoplasmic reticulum (ER)-resident kinase Perk, resulting in the phosphorylation of eIF2␣ and the adaptive modulation of protein synthesis and gene expression through a signal transduction pathway referred to as the integrated stress response (ISR) (35), an arm of the unfolded protein response (UPR) that facilitates the cellular adaptation t...

Tumor Stress Inside Out: Cell-Extrinsic Effects of the Unfolded Protein Response in Tumor Cells Modulate the Immunological Landscape of the Tumor Microenvironment

“…PERK signaling also supports tumor growth during conditions of ER stress. The inactivation of ER stress signaling by mutations of PERK, or by the introduction of a dominantnegative PERK, in mouse fibroblasts and human colon cancer cells results in tumors that are smaller, grow less rapidly, and display impaired angiogenic ability when grafted into immunodeficient mice (20,36). Taken together, these results underscore the key contribution of the UPR in the growth and progression of solid tumors of diverse origins.…”

Regulation of autophagy by ATF4 in response to severe hypoxia

“…Previous reports have established that the transcription factor ATF4 has a regulatory role in the cellular response to ER stress and amino-acid starvation (Averous et al, 2004;Ohoka et al, 2005). Activating transcription factor 4 transcriptionally upregulates the expression of ER chaperones and also the proapoptotic genes: CHOP and SKIP3 (Harding et al, 2000;Blais et al, 2006). Thus, ATF4 regulates both prosurvival and proapoptotic signalling during ER stress, however, the pathways that can shift this balance either towards survival or apoptosis still need to be characterized in detail.…”

“…Earlier studies showed the importance of the PERK pathway for tumour progression and the response to UPR (Blais et al, 2006). The adaptation of cells to chronic hypoxic stress requires translational attenuation by phosphorylation of eukaryotic initiation factor 2a by PERK Wu et al, 2006).…”

Generation and characterization of an analog-sensitive PERK allele

“…8,10 Among these is the primary UPR effector PERK, which has been characterized for its role in tumor growth, cell migration, metastasis, angiogenesis, survival of ECM-detached cells, and the epithelialmesenchymal transition. [11][12][13][14][15][16][17] In light of these pro-tumorigenic effects, there has been significant interest in developing cancer therapeutics that target PERK activity, and in defining the molecular mechanisms that underlie PERK function. 18,19 To further interrogate PERK-signaling networks, we have generated an analog-sensitive PERK allele that specifically binds N 6 -alkylated ATP analogs.…”