Date of Award
Doctor of Philosophy
Hearing loss or deafness, in its most serious form, affects an estimated 28 million people in America. One of the forms of hearing loss, known as ototoxicity, refers to damage to the ear (-oto) due to xenobiotics. Cisplatin is the most widely used antineoplastic agent in the treatment of various solid tumors. Cisplatin toxicity can lead to severe effects on the kidneys, nervous system and auditory system which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by hydration and diuresis, cisplatin-induced ototoxicity is permanent and there is currently no approved treatment for this condition. Previous studies have shown that the generation of reactive oxygen species (ROS) is a critical event that initiates damage to the outer hair cells (OHCs), stria vascularis (SVA) and spiral ganglion cells (SG) of the cochlea, leading to hearing loss after cisplatin treatment. However, the mechanism(s) underlying the transition from ROS generation to the manifestation of ototoxicity is (are) not clearly defined. Recent studies have also implicated inflammatory pathways in cisplatin-induced cell death. Various transcription factors have been linked to the induction of inflammation mediated by cisplatin in the cochlea. Recent study demonstrate that cisplatin activates signal transducer and activator of transcription 1 (STAT1) a transcription factor implicated in inflammation, which mediates damage to utricular hair cell and could also confer cisplatin-induced hearing loss. The aim of this study is to further define a role of STAT1 in cochlear inflammation and in cisplatin-mediated ototoxicity. Based on preliminary data, we hypothesize that STAT1 plays an integral role in cisplatin-mediated inflammation and hearing loss. Our data show that STAT1 couples ROS to the inflammatory process in the cochlea. The major source of ROS appears to be the NOX3 NADPH oxidase system, knockdown of which by short interfering (si)RNA reduces STAT1 activation by cisplatin and alleviates hearing loss. Activation of STAT1 by cisplatin involves phosphorylation of Serine 727 by mitogen activated protein kinases such as extracellular signal regulated kinase (ERK) 1/2 and p38. Knockdown of STAT1 by trans-tympanic administration of siRNA reduces damage to OHCs and protects against cisplatin-induced hearing loss in rats. STAT1 siRNA attenuates the production of inflammatory mediators, such as tumor necrosis factor- α (TNF-α), and reduces the recruitment of inflammatory cells to the cochlea. Furthermore, inhibition of TNF-α by trans-tympanic administration of etanercept, a clinically used TNF-α antagonist, protects against OHC damage and cisplatin-induced hearing loss. These data suggest that targeting STAT1 or the inflammatory genes it regulates could serve as useful strategies for preventing cisplatin-induced hearing loss and improve the overall quality of life of cancer patients.
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