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Control of HIF-1 Expression by eIF2 Phosphorylation–Mediated Translational Repression

Departments of ¹ Cancer Biology, ² Urology, ³ Biochemistry and Molecular Biology and ⁴ Thoracic/Head and Neck Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: David McConkey, Departments of Urology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8591; Fax: 713-792-8747; E-mail: dmcconke{at}mdanderson.org.

Key Words: Bortezomib • NPI-0052 • HIF-1 • VEGF • ER stress • prostate cancer

Hypoxia inducible factor 1 (HIF-1) plays a central role in regulating tumor angiogenesis via its effects on vascular endothelial growth factor (VEGF) transcription, and its expression is regulated through proteasome-mediated degradation. Paradoxically, previous studies have shown that proteasome inhibitors (PI) block tumor angiogensis by reducing VEGF expression, but the mechanisms have not been identified. Here, we report that PIs down-regulated HIF-1 protein levels and blocked HIF-1 transcriptional activity in human prostate cancer cells. PIs induced phosphorylation of the translation initiation factor 2 (eIF2), which caused general translational repression to inhibit HIF-1 expression. Furthermore, PIs induced HIF-1 accumulation in LNCaP-Pro5 cells depleted of eIF2 via siRNA transfection and in MEFs expressing a phosphorylation-deficient mutant form of eIF2. Finally, PIs failed to induce eIF2 phosphorylation or translational attenuation in DU145 or 253JB-V cells, and, in these cells, PIs promoted HIF-1 accumulation. Our data established that PIs down-regulated HIF-1 expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2 and inhibiting HIF-1 translation. [Cancer Res 2009;69(5):1836–43]