Papers of the Week

Chemotherapy-induced painful peripheral neuropathy (CIPN) is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which CIPN develops has remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha (HIF1A) is a transcription factor that is known to reprogram cellular metabolism. Furthermore, HIF1A protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilize the expression of HIF1A leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilize the expression of HIF1A. Moreover, knockdown of HIF1A, inhibition of HIF1A binding to its response element or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of HIF1A expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of HIF1A expression as the molecular mechanism by which bortezomib initiates CIPN. Crucially these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms.