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Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

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Abstract

The PI3K/Akt signaling pathway is involved in mediating survival of sensory hair cells. Here, we investigated the involvement of PI3K/Akt in noise-induced hearing loss in both temporary and permanent threshold shift noise models. The PI3K regulatory subunit p85α and phosphorylation of Akt on serine 473 (p-Akt S473) are downregulated in sensory hair cells, including both outer and inner hair cells, and supporting cells of the mouse organ of Corti 1 h after exposure to permanent-threshold-shift-inducing noise (PTS noise), but not with temporary-threshold-shift-inducing noise (TTS noise). In contrast, the PI3K catalytic subunit p110α and phosphorylation of Akt on threonine 308 (p-Akt T308) do not change with PTS or TTS noise. Additionally, mice pretreated with p85α small interfering RNA (siRNA) have decreased expression of p-Akt1 (S473) in their sensory hair cells and increased sensitivity to TTS noise-induced hearing loss. Finally, Akt1-knockout mice also have enhanced sensitivity to TTS noise-induced hearing loss. In conclusion, this study suggests that endogenous PI3K/Akt signaling is an intrinsic protective mechanism of the inner ear. Blockade of PI3K/Akt signaling pathways increases sensitivity to TTS noise-induced hearing loss.

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References

  • Agarwal E, Brattain MG, Chowdhury S (2013) Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal 25:1711–1719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551

    PubMed Central  CAS  PubMed  Google Scholar 

  • Breuleux M, Klopfenstein M, Stephan C, Doughty CA, Barys L, Maira SM, Kwiatkowski D, Lane HA (2009) Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 8:742–753

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  CAS  PubMed  Google Scholar 

  • Chen FQ, Zheng HW, Hill K, Sha SH (2012) Traumatic Noise Activates Rho-Family GTPases through Transient Cellular Energy Depletion. J Neurosci 32:12421–12430

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ (2001) Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276:38349–38352

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, Pak K, Lin B, Webster N, Ryan AF (2006) A PI3K pathway mediates hair cell survival and opposes gentamicin toxicity in neonatal rat organ of Corti. J Assoc Res Otolaryngol 7:373–382

    Article  PubMed Central  PubMed  Google Scholar 

  • Concannon CG, Tuffy LP, Weisova P, Bonner HP, Davila D, Bonner C, Devocelle MC, Strasser A, Ward MW, Prehn JH (2010) AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis. J Cell Biol 189:83–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fujiwara T, Hato N, Nakagawa T, Tabata Y, Yoshida T, Komobuchi H, Takeda S, Hyodo J, Hakuba N, Gyo K (2008) Insulin-like growth factor 1 treatment via hydrogels rescues cochlear hair cells from ischemic injury. Neuroreport 19:1585–1588

    Article  CAS  PubMed  Google Scholar 

  • Haake SM, Dinh CT, Chen S, Eshraghi AA, Van De Water TR (2009) Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling. Hear Res 255:22–32

    Article  CAS  PubMed  Google Scholar 

  • Harding GW, Bohne BA, Vos JD (2005) The effect of an age-related hearing loss gene (Ahl) on noise-induced hearing loss and cochlear damage from low-frequency noise. Hear Res 204:90–100

    Article  PubMed  Google Scholar 

  • Hayashi Y, Yamamoto N, Nakagawa T, Ito J (2013) Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice. Mol Cell Neurosci 56C:29–38

    Article  Google Scholar 

  • Hemmings BA, Restuccia DF (2012) PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol 4:a011189

    Article  PubMed Central  PubMed  Google Scholar 

  • Jiang H, Sha SH, Schacht J (2006) Kanamycin alters cytoplasmic and nuclear phosphoinositide signaling in the organ of Corti in vivo. J Neurochem 99:269–276

    Article  CAS  PubMed  Google Scholar 

  • Laine J, Kunstle G, Obata T, Noguchi M (2002) Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family. J Biol Chem 277:3743–3751

    Article  CAS  PubMed  Google Scholar 

  • Lallemend F, Hadjab S, Hans G, Moonen G, Lefebvre PP, Malgrange B (2005) Activation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons. J Cell Sci 118:4511–4525

    Article  CAS  PubMed  Google Scholar 

  • McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S (2008) Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 68:1618–1624

    Article  CAS  PubMed  Google Scholar 

  • Nagashima R, Yamaguchi T, Kuramoto N, Ogita K (2011) Acoustic overstimulation activates 5′-AMP-activated protein kinase through a temporary decrease in ATP level in the cochlear spiral ligament prior to permanent hearing loss in mice. Neurochem Int 59:812–820

    Article  CAS  PubMed  Google Scholar 

  • Nagy I, Monge A, Albinger-Hegyi A, Schmid S, Bodmer D (2005) NF-kappaB is required for survival of immature auditory hair cells in vitro. JARO 6:260–268

    Article  PubMed Central  PubMed  Google Scholar 

  • Nagy I, Caelers A, Monge A, Bonabi S, Huber AM, Bodmer D (2007) NF-kappaB-dependent apoptotic hair cell death in the auditory system. Audiol Neurootol 12:209–220

    Article  PubMed  Google Scholar 

  • Oishi N, Chen FQ, Zheng HW, Sha SH (2013) Intra-tympanic delivery of short interfering RNA into the adult mouse cochlea. Hearing Res 296:36–41

    Article  CAS  Google Scholar 

  • Paez J, Sellers WR (2003) PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res 115:145–167

    Article  CAS  PubMed  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  CAS  PubMed  Google Scholar 

  • Sha SH, Chen FQ, Schacht J (2010) PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse. Hear Res 264:86–92

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vadlakonda L, Dash A, Pasupuleti M, Anil Kumar K, Reddanna P (2013) The Paradox of Akt-mTOR Interactions. Front Oncol 3:165

    PubMed Central  PubMed  Google Scholar 

  • Varela-Nieto I, de la Rosa EJ, Valenciano AI, Leon Y (2003) Cell death in the nervous system: lessons from insulin and insulin-like growth factors. Mol Neurobiol 28:23–50

    Article  CAS  PubMed  Google Scholar 

  • Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR (1998) Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J 331(Pt 1):299–308

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 23:8596–8607

    CAS  PubMed  Google Scholar 

  • Yuan H, Chen J, Hill K, Lemasters J, Yang SM, Sha SH (2014) Autophay attenuates noise-induced hearing loss by reducing oxidative stress. ARS, manuscript submitted

  • Zheng HW, Chen J, Sha SH (2014) Receptor-interacting protein kinases modulate noise-induced sensory hair cell death. Cell Death Dis 5:e1262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The research project described was supported by grant R01 DC009222 from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health. This work was conducted in part in the WR Building at MUSC in renovated space supported by grant C06 RR014516. Animals were housed in MUSC CRI animal facilities supported by grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. We thank Dr. Jochen Schacht for his valuable comments on the manuscript.

Author Disclosure Statement

The data contained in the manuscript have not been previously published and have not been submitted elsewhere and will not be submitted elsewhere while under review. All research protocols were approved by the Institutional Animal Care and Use Committee at the Medical University of South Carolina (MUSC) or by the University of Michigan (UM) Committee on Use and Care of Animals. Animal care was under the supervision of Division of Laboratory Animal Resources at MUSC or of Unit for Laboratory Animal Medicine at UM. All authors have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data.

Conflict of Interest

There are no conflicts of interest for any of the authors.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA

    Jun Chen, Hu Yuan, Kayla Hill & Su-Hua Sha

  2. Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, 48109, USA

    Andra E. Talaska

  3. Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Jun Chen

  4. Department of Otolaryngology-Head and Neck Surgery, Chinese PLA General Hospital, Beijing, 100853, P.R. China

    Hu Yuan

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  1. Jun Chen
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  2. Hu Yuan
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  3. Andra E. Talaska
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  4. Kayla Hill
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  5. Su-Hua Sha
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Correspondence to Su-Hua Sha.

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Chen, J., Yuan, H., Talaska, A.E. et al. Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling. JARO 16, 347–356 (2015). https://doi.org/10.1007/s10162-015-0508-x

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  • DOI: https://doi.org/10.1007/s10162-015-0508-x

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