Upregulation of the Kank1 gene-induced brain glioma apoptosis and blockade of the cell cycle in G0/G1 phase

Guo,Xiaohang; Fan,Wenhai; Bian,Xinchao; Ma,Dihui

doi:10.3892/ijo.2014.2247

Upregulation of the Kank1 gene-induced brain glioma apoptosis and blockade of the cell cycle in G0/G1 phase

Authors:
- Xiaohang Guo
- Wenhai Fan
- Xinchao Bian
- Dihui Ma
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Affiliations: Department of Neurology, The First Hospital of Jilin University, Changchun 130021, P.R. China, Department of Neurosurgery, The Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, P.R. China, Department of Neurosurgery, Zibo Central Hospital, Zibo 255000, P.R. China
Published online on: January 8, 2014 https://doi.org/10.3892/ijo.2014.2247
Pages: 797-804

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Abstract

The Kank1 gene is one of the important members of the Kank gene family. As an important adaptor protein, Kank1 plays a significant role in the genesis and development of many malignant tumors. It was recently discovered that the Kank1 gene is a new cancer suppressor, and its expression is significantly downregulated or it is not expressed in kidney cancer, bladder cancer, prostate cancer, lung cancer and breast cancer. However, no report on the role of Kank1 in the genesis of brain glioma is available to date. In this study, we found significantly lower expression of the Kank1 gene in human brain glioma cells compared to the other cells evaluated. We used RNA interference techniques to silence Kank1 gene expression and found acceleration of tumor cell proliferation. However, when the Kank1 gene was upregulated, cell apoptosis occurred and the cell cycle was blocked in the G0/G1 phase. Also, we found that upregulating the Kank1 gene may result in the change of mitochondrial membrane potential, and the regulation of Bax and Bcl-2 may promote the mitochondria to release cytochrome C so as to activate Caspase-9 and -3. Thus, the human brain glioma apoptosis induced by upregulation of the Kank1 gene is closely relevant to the mitochondrial pathway.

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1.	Cordner R, Black KL and Wheeler CJ: Exploitation of adaptive evolution in glioma treatment. CNS Oncol. 2:171–179. 2013. View Article : Google Scholar : PubMed/NCBI
2.	Hess KR, Broglio KR and Bondy ML: Adult glioma incidence trends in the United States, 1977–2000. Cancer. 101:2293–2299. 2004.PubMed/NCBI
3.	Eyüpoglu IY, Buchfelder M and Savaskan NE: Surgical resection of malignant gliomas - role in optimizing patient outcome. Nat Rev Neurol. 9:141–151. 2013.PubMed/NCBI
4.	Stummer W and Kamp MA: The importance of surgical resection in malignant glioma. Curr Opin Neurol. 22:645–649. 2009. View Article : Google Scholar : PubMed/NCBI
5.	Mrugala MM: Advances and challenges in the treatment of glioblastoma: a clinician’s perspective. Discov Med. 15:221–230. 2013.PubMed/NCBI
6.	Norden AD and Wen PY: Glioma therapy in adults. Neurologist. 12:279–292. 2006. View Article : Google Scholar : PubMed/NCBI
7.	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
8.	Demoulin JB, Medves S, Toffalini F, Essaghir A, Kallin A, Montano C, Velghe A and Duhoux F: Role of PDGF and FGF receptors in cancer. Bull Mem Acad R Med Belg. 165:310–315. 2010.(In French).
9.	Kakinuma N, Zhu Y, Wang Y, Roy BC and Kiyama R: Kank proteins: structure, functions and diseases. Cell Mol Life Sci. 66:2651–2659. 2009. View Article : Google Scholar : PubMed/NCBI
10.	Lo KC, Stein LC, Panzarella JA, Cowell JK and Hawthorn L: Identification of genes involved in squamous cell carcinoma of the lung using synchronized data from DNA copy number and transcript expression profiling analysis. Lung Cancer. 59:315–331. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Sato M, Takahashi K, Nagayama K, Arai Y, Ito N, Okada M, Minna JD, Yokota J and Kohno T: Identification of chromosome arm 9p as the most frequent target of homozygous deletions in lung cancer. Genes Chromosomes Cancer. 44:405–414. 2005. View Article : Google Scholar : PubMed/NCBI
12.	Kohno T, Otsuka A, Girard L, Sato M, Iwakawa R, Ogiwara H, Sanchez-Cespedes M, Minna JD and Yokota J: A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene. Genes Chromosomes Cancer. 49:342–352. 2010.PubMed/NCBI
13.	Chan WH: Citrinin induces apoptosis in mouse embryonic stem cells. IUBMB Life. 60:171–179. 2008. View Article : Google Scholar : PubMed/NCBI
14.	Tomiyama A, Tachibana K, Suzuki K, Seino S, Sunayama J, Matsuda KI, Sato A, Matsumoto Y, Nomiya T, Nemoto K, Yamashita H, Kayama T, Ando K and Kitanaka C: MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death. Cell Death Dis. 1:e602010. View Article : Google Scholar : PubMed/NCBI
15.	Tang B, Zhang Y, Liang R, Yuan P, Du J, Wang H and Wang L: Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway. Int J Mol Med. 28:1077–1085. 2011.
16.	Sarkar S, Roy BC, Hatano N, Aoyagi T, Gohji K and Kiyama R: A novel ankyrin repeat-containing gene (Kank) located at 9p24 is a growth suppressor of renal cell carcinoma. J Biol Chem. 277:36585–36591. 2002. View Article : Google Scholar : PubMed/NCBI
17.	Zhu Y, Kakinuma N, Wang Y and Kiyama R: Kank proteins: a new family of ankyrin-repeat domain-containing proteins. Biochim Biophys Acta. 1780:128–133. 2008. View Article : Google Scholar : PubMed/NCBI
18.	Roy BC, Kakinuma N and Kiyama R: Kank attenuates actin remodeling by preventing interaction between IRSp53 and Rac1. J Cell Biol. 184:253–267. 2009. View Article : Google Scholar : PubMed/NCBI
19.	Kakinuma N, Roy BC, Zhu Y, Wang Y and Kiyama R: Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K-Akt signaling. J Cell Biol. 181:537–549. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Matthews GM, Newbold A and Johnstone RW: Intrinsic and extrinsic apoptotic pathway signaling as determinants of histone deacetylase inhibitor antitumor activity. Adv Cancer Res. 116:165–197. 2012. View Article : Google Scholar : PubMed/NCBI
21.	Nieminen AI, Partanen JI and Klefstrom J: c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc. Cell Cycle. 6:2464–2472. 2007. View Article : Google Scholar : PubMed/NCBI
22.	Ghobrial IM, Witzig TE and Adjei AA: Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 55:178–194. 2005. View Article : Google Scholar : PubMed/NCBI
23.	Renault TT, Teijido O, Antonsson B, Dejean LM and Manon S: Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x(L): keep your friends close but your enemies closer. Int J Biochem Cell Biol. 45:64–67. 2013. View Article : Google Scholar : PubMed/NCBI
24.	Mattson MP and Kroemer G: Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med. 9:196–205. 2003. View Article : Google Scholar : PubMed/NCBI
25.	Lindsay J, Esposti MD and Gilmore AP: Bcl-2 proteins and mitochondria - specificity in membrane targeting for death. Biochim Biophys Acta. 1813:532–539. 2011. View Article : Google Scholar : PubMed/NCBI
26.	Saito M, Korsmeyer SJ and Schlesinger PH: BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol. 2:553–555. 2000. View Article : Google Scholar : PubMed/NCBI
27.	Yuan S and Akey CW: Apoptosome structure, assembly, and procaspase activation. Structure. 21:501–515. 2013. View Article : Google Scholar : PubMed/NCBI
28.	McIlwain DR, Berger T and Mak TW: Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 5:a0086562013. View Article : Google Scholar : PubMed/NCBI
29.	Riedl SJ and Shi Y: Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 5:897–907. 2004. View Article : Google Scholar : PubMed/NCBI
30.	Williams GT: Programmed cell death: apoptosis and onco-genesis. Cell. 65:1097–1098. 1991. View Article : Google Scholar
31.	Evan G and Littlewood T: A matter of life and cell death. Science. 281:1317–1322. 1998. View Article : Google Scholar : PubMed/NCBI
32.	Wang XM, Cui JW, Li W, Cai L, Song W and Wang GJ: Silencing of the COPS3 gene by siRNA reduces proliferation of lung cancer cells most likely via induction of cell cycle arrest and apoptosis. Asian Pac J Cancer Prev. 13:1043–1048. 2012. View Article : Google Scholar : PubMed/NCBI
33.	Powathil GG, Gordon KE, Hill LA and Chaplain MA: Modelling the effects of cell-cycle heterogeneity on the response of a solid tumour to chemotherapy: biological insights from a hybrid multiscale cellular automaton model. J Theor Biol. 308:1–19. 2012. View Article : Google Scholar