Connexin 43 Acts as a Proapoptotic Modulator in Cisplatin-Induced Auditory Cell Death.
Gap junction coupling is known to play a role in intercellular communication by the Good Samaritan effect or bystander effect. Nonjunctional connexins (Cxs) may also play certain gap junction-independent roles in cell death or survival. The purpose of the present study was to investigate the role of junctional and nonjunctional Cxs in ototoxic drug-induced auditory cell death by focusing on Cx43 in the cochlea.



Nonjunctional Cx43 conditions were prepared by low confluence culture (5 × 103/cm2) or a trafficking inhibitor, brefeldin A (BFA), in auditory cells, and short lengthened Cx43s with amino-terminal (NT; amino acids 1-256) or carboxy-terminal (CT; amino acids 257-382) were transfected into Cx-deficient HeLa cells to avoid gap junction formation. Knockdown of nonchannel Cx43 (small interfering RNA [siRNA]) inhibited Cis-diamminedichloroplatinum (cisplatin)-induced cell death regardless of gap junction formation; however, a gap junction blocker, 18 alpha-glycyrrhetinic acid (18α-GA), showed inhibitory effect only under the junctional condition. BFA did not show any additive influence on the inhibitory effect of siRNA Cx43. Shortened Cx43-transfected HeLa cells also resulted in a significant increase in cell death under cisplatin. In the animal studies with cisplatin-treated rats, hearing thresholds of auditory brainstem response were significantly preserved by a gap junction blocker, carbenoxolone, showing much more preserved stereocilia of hair cells in scanning electron microscopic findings. Innovation and Conclusion: Cx43 plays a proapoptotic role in cisplatin-induced auditory cell death in both junctional and nonjunctional conditions. Targeting the Cx-mediated signaling control may be helpful in designing new therapeutic strategies for drug-induced ototoxicity. Antioxid. Redox Signal. 25, 623-636.
1 Department of Otolaryngology, Ajou University School of Medicine , Suwon, Republic of Korea.
Yeon Ju
YJ
Kim
2 Department of Rural and Biosystems Engineering, Chonnam National University , Gwangju, Republic of Korea.
Jangho
J
Kim
1 Department of Otolaryngology, Ajou University School of Medicine , Suwon, Republic of Korea.
Young Sun
YS
Kim
3 Department of Medical Sciences, The Graduate School, Ajou University , Suwon, Republic of Korea.
Beomyong
B
Shin
1 Department of Otolaryngology, Ajou University School of Medicine , Suwon, Republic of Korea.
Oak-Sung
OS
Choo
1 Department of Otolaryngology, Ajou University School of Medicine , Suwon, Republic of Korea.
Jong Joo
JJ
Lee
1 Department of Otolaryngology, Ajou University School of Medicine , Suwon, Republic of Korea.|3 Department of Medical Sciences, The Graduate School, Ajou University , Suwon, Republic of Korea.
Yun-Hoon
YH
Choung
D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020126:Brefeldin A / Q000008:administration & dosage; D002450:Cell Communication / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D010766:Phosphorylation; D051381:Rats
D018031:Connexin 43; D020126:Brefeldin A; D002945:Cisplatin