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Connexin 43 Acts as a Pro-Apoptotic Modulator in Cisplatin-induced Auditory Cell Death

Kim, Yeon Ju; Kim, Young Sun; Shin, Beomyong; Choo, Oak-Sung; Choung, Yun-Hoon
Department of Otolaryngology
Introduction Gap junction (GJ) coupling may play a role for intercellular communication by the “Good Samaritan effect” or “bystander effect” under pathological conditions. Non-junctional connexins (Cxs) also may play some gap junction-independent roles in cell death or survival. The purposes of this study were to investigate the role of non-junctional Cxs in ototoxic drug-induced apoptosis of auditory cells and to evaluate the effect of GJ inhibitors on cisplatin-induced hearing loss using in vivo animal models.

Materials and Methods Non-junctional Cx43 proteins in HEI-OC1 cells were prepared with three techniques. 1) Low confluence culture (< 1X104/cm2). 2) Construction of short lengthened Cx43 - Cx43-NT (amino acid 1-256, membrane domain) and Cx43-CT (amino acid 257-382, cytoplasmic domain). 3) Brefeldin A (BFA), an ER-Golgi trafficking inhibitor. A live/dead cell viability assay and western blotting were done under knock-down conditions (siRNA-Cx43). Additionally, For in vivo animal studies, carbenoxolone (CBX, 50 mg/kg) is intraperitoneally injected to rats treated with cisplatin (16 mg/kg). Auditory brainstem response and morphologic analysis were done with immunohistochemistry.

Results Knock down of non-channel Cx43 (siRNA) inhibited cisplatin-induced cell death in MTT assay and Western blot. This finding was not changed by disruption of Cx43 trafficking with BFA. HeLa cells expressing the Cx43-FL (full length), Cx43-NT or Cx43-CT showed enhanced sensitivity to cisplatin compared to Mock cells. In animal studies with cisplatin-treated rats, hearing thresholds of auditory brainstem response were significantly preserved by a gap junction blocker, CBX, showing much more preserved stereocilia of hair cells in scanning electron microscopic findings.

Conclusion Cx43 plays a pro-apoptotic role in cisplatin-induced auditory cell death in both junctional and non-junctional conditions. Targeting the Cx-mediated signaling control may be helpful in designing new therapeutic strategies for drug-induced ototoxicity. may be necessary for designing new therapeutic strategies for drug-induced ototoxicity.
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