VDAC upregulation and αTAT1‑mediated α‑tubulin acetylation contribute to tanespimycin‑induced apoptosis in Calu‑1 cells

Wang,Qilin; Liu,Xiangguo

doi:10.3892/or.2020.7789

VDAC upregulation and αTAT1‑mediated α‑tubulin acetylation contribute to tanespimycin‑induced apoptosis in Calu‑1 cells

Authors:
- Qilin Wang
- Xiangguo Liu
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Affiliations: School of Life Sciences, Liaocheng University, Liaocheng, Shandong 252059, P.R. China, School of Life Sciences, Shandong University, Qingdao, Shandong 266237, P.R. China
Published online on: October 5, 2020 https://doi.org/10.3892/or.2020.7789
Pages: 2725-2734

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Abstract

Voltage‑dependent anion channel 1 (VDAC1) functions as a porin in the mitochondrial outer membrane (MOM) and plays important roles in mitochondria‑mediated cell apoptosis. VDAC1 interacts with a variety of proteins, such as Bcl‑2 family proteins, hexose kinase (HK), adenine nucleotide translocase (ANT) and α‑tubulin. However, the association between VDAC1 and α‑tubulin, particularly between VDAC1 and acetylated α‑tubulin (Ac‑α‑tubulin), in apoptosis remains unclear. The present study revealed that the heat shock protein 90 inhibitor, tanespimycin, induced VDAC1 upregulation and α‑tubulin acetylation during Calu‑1 cell apoptosis in human lung cancer. Hsp90 mediated the expression level of VDAC1, and the acetylation of α‑tubulin was enhanced in an α‑tubulin acetyltransferase 1 (αTAT1)‑dependent manner following an increase in VDAC1 expression. Docetaxel, as an inhibitor of microtubules, augmented the expression of Ac‑α‑tubulin, VDAC1 and Bax induced by tanespimycin and increased the degree of caspase activation. Immunoprecipitation (IP) experiments revealed that Ac‑α‑tubulin, α‑tubulin and VDAC1 were co‑precipitated in the IP complex, in which α‑tubulin expression was decreased and VDAC1 proteins were oligomerized, and that the p‑AKT/glycogen synthase kinase 3β (GSK3β) signalling pathway mediated the opening of VDAC1. Therefore, it can be asserted that the acetylation of α‑tubulin and VDAC1 upregulation or oligomerization induced by tanespimycin may lead to mitochondrial permeability and consequently induce the apoptosis of lung cancer cells. These findings provide evidence for the use of a combination of drugs that target VDAC1 and tubulin to induce tumour cell apoptosis.

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1	Shoshan-Barmatz V, Krelin Y and Chen Q: VDAC1 as a player in mitochondria-mediated apoptosis and target for modulating apoptosis. Curr Med Chem. 24:4435–4446. 2017.PubMed/NCBI
2	Bayrhuber M, Meins T, Habeck M, Becker S, Giller K, Villinger S, Vonrhein C, Griesinger C, Zweckstetter M and Zeth K: Structure of the human voltage-dependent anion channel. Proc Natl Acad Sci USA. 105:15370–15375. 2008. View Article : Google Scholar : PubMed/NCBI
3	Hiller S, Garces RG, Malia TJ, Orekhov VY, Colombini M and Wagner G: Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science. 321:1206–1210. 2008. View Article : Google Scholar : PubMed/NCBI
4	Maldonado EN, Sheldon KL, DeHart DN, Patnaik J, Manevich Y, Townsend DM, Bezrukov SM, Rostovtseva TK and Lemasters JJ: Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: Regulation by free tubulin and erastin. J Biol Chem. 288:11920–11929. 2013. View Article : Google Scholar : PubMed/NCBI
5	Shuvo SR, Ferens FG and Court DA: The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape. Biochim Biophys Acta. 1858:1350–1361. 2016. View Article : Google Scholar : PubMed/NCBI
6	Keinan N, Tyomkin D and Shoshan-Barmatz V: Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. Mol Cell Biol. 30:5698–5709. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tian M, Xie Y, Meng Y, Ma W, Tong Z, Yang X, Lai S, Zhou Y, He M and Liao Z: Resveratrol protects cardiomyocytes against anoxia/reoxygenation via dephosphorylation of VDAC1 by Akt-GSK3 β pathway. Eur J Pharmacol. 843:80–87. 2019. View Article : Google Scholar : PubMed/NCBI
8	Heslop KA, Rovini A, Hunt EG, Fang D, Morris ME, Christie CF, Gooz MB, DeHart DN, Dang Y, Lemasters JJ and Maldonado EN: JNK activation and translocation to mitochondria mediates mitochondrial dysfunction and cell death induced by VDAC opening and sorafenib in hepatocarcinoma cells. Biochem Pharmacol. 171:1137282020. View Article : Google Scholar : PubMed/NCBI
9	Abu-Hamad S, Zaid H, Israelson A, Nahon E and Shoshan-Barmatz V: Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: Mapping the site of binding. J Biol Chem. 283:13482–13490. 2008. View Article : Google Scholar : PubMed/NCBI
10	Shoshan-Barmatz V, Ben-Hail D, Admoni L, Krelin Y and Tripathi SS: The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim Biophys Acta. 1848:2547–2575. 2015. View Article : Google Scholar : PubMed/NCBI
11	Mazure NM: VDAC in cancer. Biochim Biophys Acta Bioenerg. 1858:665–673. 2017. View Article : Google Scholar : PubMed/NCBI
12	Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L, Araujo N, Pinna G, Larochette N, Zamzami N, et al: Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene. 27:4221–4232. 2008. View Article : Google Scholar : PubMed/NCBI
13	Matsubara H, Tanaka R, Tateishi T, Yoshida H, Yamaguchi M and Kataoka T: The human Bcl-2 family member Bcl-rambo and voltage-dependent anion channels manifest a genetic interaction in Drosophila and cooperatively promote the activation of effector caspases in human cultured cells. Exp Cell Res. 381:223–234. 2019. View Article : Google Scholar : PubMed/NCBI
14	Pastorino JG, Hoek JB and Shulga N: Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 65:10545–10554. 2005. View Article : Google Scholar : PubMed/NCBI
15	Head SA, Shi W, Zhao L, Gorshkov K, Pasunooti K, Chen Y, Deng Z, Li RJ, Shim JS, Tan W, et al: Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci USA. 112:E7276–E7285. 2015. View Article : Google Scholar : PubMed/NCBI
16	Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM and Sackett DL: Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci USA. 105:18746–18751. 2008. View Article : Google Scholar : PubMed/NCBI
17	Rovini A: Tubulin-VDAC interaction: Molecular basis for mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy. Front Physiol. 10:6712019. View Article : Google Scholar : PubMed/NCBI
18	Shoshan-Barmatz V, Mizrachi D and Keinan N: Oligomerization of the mitochondrial protein VDAC1: From structure to function and cancer therapy. Prog Mol Biol Transl Sci. 117:303–334. 2013. View Article : Google Scholar : PubMed/NCBI
19	Xie Q, Wondergem R, Shen Y, Cavey G, Ke J, Thompson R, Bradley R, Daugherty-Holtrop J, Xu Y, Chen E, et al: Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion. Proc Natl Acad Sci USA. 108:4105–4110. 2011. View Article : Google Scholar : PubMed/NCBI
20	Wang Q, Sun W, Hao X, Li T, Su L and Liu X: Down-regulation of cellular FLICE-inhibitory protein (Long Form) contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells. Cancer Cell Int. 12:542012. View Article : Google Scholar : PubMed/NCBI
21	Liu X, Yue P, Zhou Z, Khuri FR and Sun SY: Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst. 96:1769–1780. 2004. View Article : Google Scholar : PubMed/NCBI
22	Chatterjee M, Jain S, Stühmer T, Andrulis M, Ungethüm U, Kuban RJ, Lorentz H, Bommert K, Topp M, Krämer D, et al: STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival. Blood. 109:720–728. 2007. View Article : Google Scholar : PubMed/NCBI
23	Abu-Hamad S, Sivan S and Shoshan-Barmatz V: The expression level of the voltage-dependent anion channel controls life and death of the cell. Proc Natl Acad Sci USA. 103:5787–5792. 2006. View Article : Google Scholar : PubMed/NCBI
24	Su L, Liu G, Hao X, Zhong N, Zhong D, Liu X and Singhal S: Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 47:2471–2478. 2011. View Article : Google Scholar : PubMed/NCBI
25	Chacko AD, Liberante F, Paul I, Longley DB and Fennell DA: Voltage dependent anion channel-1 regulates death receptor mediated apoptosis by enabling cleavage of caspase-8. BMC Cancer. 10:3802010. View Article : Google Scholar : PubMed/NCBI
26	Li L and Yang XJ: Tubulin acetylation: Responsible enzymes, biological functions and human diseases. Cell Mol Life Sci. 72:4237–4255. 2015. View Article : Google Scholar : PubMed/NCBI
27	Park MA, Zhang G, Mitchell C, Rahmani M, Hamed H, Hagan MP, Yacoub A, Curiel DT, Fisher PB, Grant S and Dent P: Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95. Mol Cancer Ther. 7:2633–2648. 2008. View Article : Google Scholar : PubMed/NCBI
28	Shida T, Cueva JG, Xu Z, Goodman MB and Nachury MV: The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc Natl Acad Sci USA. 107:21517–21522. 2010. View Article : Google Scholar : PubMed/NCBI
29	Eshun-Wilson L, Zhang R, Portran D, Nachury MV, Toso DB, Löhr T, Vendruscolo M, Bonomi M, Fraser JS and Nogales E: Effects of α-tubulin acetylation on microtubule structure and stability. Proc Natl Acad Sci USA. 116:10366–10371. 2019. View Article : Google Scholar : PubMed/NCBI
30	No M, Choi EJ and Kim IA: Targeting HER2 signaling pathway for radiosensitization: Alternative strategy for therapeutic resistance. Cancer Biol Ther. 8:2351–2361. 2009. View Article : Google Scholar : PubMed/NCBI
31	Burke PJ: Mitochondria, bioenergetics and apoptosis in cancer. Trends Cancer. 3:857–870. 2017. View Article : Google Scholar : PubMed/NCBI
32	Krüger V, Becker T, Becker L, Montilla-Martinez M, Ellenrieder L, Vögtle FN, Meyer HE, Ryan MT, Wiedemann N, Warscheid B, et al: Identification of new channels by systematic analysis of the mitochondrial outer membrane. J Cell Biol. 216:3485–3495. 2017. View Article : Google Scholar : PubMed/NCBI
33	Reif MM, Fischer M, Fredriksson K, Hagn F and Zacharias M: The N-terminal segment of the voltage-dependent anion channel: A possible membrane-bound intermediate in pore unbinding. J Mol Biol. 431:223–243. 2019. View Article : Google Scholar : PubMed/NCBI
34	Böhm R, Amodeo GF, Murlidaran S, Chavali S, Wagner G, Winterhalter M, Brannigan G and Hiller S: The structural basis for low conductance in the membrane protein VDAC upon β-NADH binding and voltage gating. Structure. 28:206–214.e4. 2020. View Article : Google Scholar : PubMed/NCBI
35	Urbani A, Giorgio V, Carrer A, Franchin C, Arrigoni G, Jiko C, Abe K, Maeda S, Shinzawa-Itoh K, Bogers JFM, et al: Purified F-ATP synthase forms a Ca²⁺-dependent high-conductance channel matching the mitochondrial permeability transition pore. Nat Commun. 10:43412019. View Article : Google Scholar : PubMed/NCBI
36	Cosentino K and García-Sáez AJ: Bax and Bak pores: Are we closing the circle? Trends Cell Biol. 27:266–275. 2017. View Article : Google Scholar : PubMed/NCBI
37	Chin HS, Li MX, Tan IKL, Ninnis RL, Reljic B, Scicluna K, Dagley LF, Sandow JJ, Kelly GL, Samson AL, et al: VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nat Commun. 9:49762018. View Article : Google Scholar : PubMed/NCBI
38	Zalk R, Israelson A, Garty ES, Azoulay-Zohar H and Shoshan-Barmatz V: Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria. Biochem J. 386:73–83. 2005. View Article : Google Scholar : PubMed/NCBI
39	Rosano C: Molecular model of hexokinase binding to the outer mitochondrial membrane porin (VDAC1): Implication for the design of new cancer therapies. Mitochondrion. 11:513–519. 2011. View Article : Google Scholar : PubMed/NCBI
40	Scharstuhl A, Mutsaers HA, Pennings SW, Russel FG and Wagener FA: Involvement of VDAC, Bax and ceramides in the efflux of AIF from mitochondria during curcumin-induced apoptosis. PLoS One. 4:e66882009. View Article : Google Scholar : PubMed/NCBI
41	Xu Z, Schaedel L, Portran D, Aguilar A, Gaillard J, Marinkovich MP, Théry M and Nachury MV: Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science. 356:328–332. 2017. View Article : Google Scholar : PubMed/NCBI
42	Taschner M, Vetter M and Lorentzen E: Atomic resolution structure of human α-tubulin acetyltransferase bound to acetyl-CoA. Proc Natl Acad Sci USA. 109:19649–19654. 2012. View Article : Google Scholar : PubMed/NCBI
43	Wang Q and Liu X: The dual functions of α-tubulin acetylation in cellular apoptosis and autophage induced by tanespimycin in lung cancer cells. Cancer Cell Int. 20:3692020. View Article : Google Scholar : PubMed/NCBI