Downregulation of mitochondrial UQCRB inhibits cancer stem cell-like properties in glioblastoma

Jung,Narae; Kwon,Ho Jeong; Jung,Hye Jin

doi:10.3892/ijo.2017.4191

Downregulation of mitochondrial UQCRB inhibits cancer stem cell-like properties in glioblastoma

Authors:
- Narae Jung
- Ho Jeong Kwon
- Hye Jin Jung
View Affiliations

Affiliations: Department of BT-Convergent Pharmaceutical Engineering, Sun Moon University, Tangjeong-myeon, Asan-si, Chungnam 336-708, Republic of Korea, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea
Published online on: November 6, 2017 https://doi.org/10.3892/ijo.2017.4191
Pages: 241-251

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma stem cell targeted therapies have become a powerful strategy for the treatment of this deadliest brain tumor. We demonstrate for the first time that downregulation of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) inhibits the cancer stem cell-like properties in human glioblastoma cells. The synthetic small molecules targeting UQCRB significantly suppressed not only the self-renewal capacity such as growth and neurosphere formation, but also the metastatic potential such as migration and invasion of glioblastoma stem‑like cells (GSCs) derived from U87MG and U373MG at subtoxic concentrations. Notably, the UQCRB inhibitors repressed c‑Met-mediated downstream signal transduction and hypoxia‑inducible factor‑1α (HIF‑1α) activation, thereby reducing the expression levels of GSC markers including CD133, Nanog, Oct4 and Sox2 in the GSCs. Furthermore, the UQCRB inhibitors decreased mitochondrial ROS generation and mitochondrial membrane potential in the GSCs, indicating that they regulate the mitochondrial function in GSCs. Indeed, the knockdown of UQCRB gene by UQCRB siRNA significantly inhibited the cancer stem cell-like phenotypes as well as the expression of stemness markers by blocking mitochondrial ROS/HIF‑1α/c‑Met pathway in U87MG GSCs. These findings suggest that UQCRB and its inhibitors could be a new therapeutic target and lead compounds for eliminating cancer stem cells in glioblastoma.

View Figures

View References

1	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
2	Lutterbach J, Guttenberger R and Pagenstecher A: Gliosarcoma: A clinical study. Radiother Oncol. 61:57–64. 2001. View Article : Google Scholar : PubMed/NCBI
3	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
4	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
5	Stavrovskaya AA, Shushanov SS and Rybalkina EY: Problems of glioblastoma multiforme drug resistance. Biochemistry (Mosc). 81:91–100. 2016. View Article : Google Scholar
6	Sundar SJ, Hsieh JK, Manjila S, Lathia JD and Sloan A: The role of cancer stem cells in glioblastoma. Neurosurg Focus. 37:E62014. View Article : Google Scholar : PubMed/NCBI
7	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
8	Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL and Yu JS: Analysis of gene expression and chemoresistance of CD133⁺ cancer stem cells in glioblastoma. Mol Cancer. 5:672006. View Article : Google Scholar
9	Cho DY, Lin SZ, Yang WK, Lee HC, Hsu DM, Lin HL, Chen CC, Liu CL, Lee WY and Ho LH: Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant. 22:731–739. 2013. View Article : Google Scholar : PubMed/NCBI
10	Kalkan R: Glioblastoma stem cells as a new therapeutic target for glioblastoma. Clin Med Insights Oncol. 9:95–103. 2015. View Article : Google Scholar : PubMed/NCBI
11	Jung HJ, Lee HB, Kim CJ, Rho JR, Shin J and Kwon HJ: Anti-angiogenic activity of terpestacin, a bicyclo sesterterpene from Embellisia chlamydospora. J Antibiot (Tokyo). 56:492–496. 2003. View Article : Google Scholar
12	Jung HJ, Shim JS, Lee J, Song YM, Park KC, Choi SH, Kim ND, Yoon JH, Mungai PT, Schumacker PT, et al: Terpestacin inhibits tumor angiogenesis by targeting UQCRB of mitochondrial complex III and suppressing hypoxia-induced reactive oxygen species production and cellular oxygen sensing. J Biol Chem. 285:11584–11595. 2010. View Article : Google Scholar : PubMed/NCBI
13	Jung HJ, Kim Y, Chang J, Kang SW, Kim JH and Kwon HJ: Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells. J Mol Med (Berl). 91:1117–1128. 2013. View Article : Google Scholar
14	Jung HJ, Kim KH, Kim ND, Han G and Kwon HJ: Identification of a novel small molecule targeting UQCRB of mitochondrial complex III and its anti-angiogenic activity. Bioorg Med Chem Lett. 21:1052–1056. 2011. View Article : Google Scholar : PubMed/NCBI
15	Jung HJ, Cho M, Kim Y, Han G and Kwon HJ: Development of a novel class of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) modulators as promising antiangiogenic leads. J Med Chem. 57:7990–7998. 2014. View Article : Google Scholar : PubMed/NCBI
16	Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F and Vescovi A: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64:7011–7021. 2004. View Article : Google Scholar : PubMed/NCBI
17	Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, Yong WH, Vinters HV, Liau LM, Lazareff JA, et al: Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells. 27:980–987. 2009. View Article : Google Scholar : PubMed/NCBI
18	Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, et al: Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 9:391–403. 2006. View Article : Google Scholar : PubMed/NCBI
19	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
20	Cheng L, Wu Q, Guryanova OA, Huang Z, Huang Q, Rich JN and Bao S: Elevated invasive potential of glioblastoma stem cells. Biochem Biophys Res Commun. 406:643–648. 2011. View Article : Google Scholar : PubMed/NCBI
21	Zhang X, Zhang W, Mao XG, Zhen HN, Cao WD and Hu SJ: Targeting role of glioma stem cells for glioblastoma multiforme. Curr Med Chem. 20:1974–1984. 2013. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, Xia S, Trageser D, Guerrero-Cázares H, Eberhart CG, et al: c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci USA. 108:9951–9956. 2011. View Article : Google Scholar : PubMed/NCBI
23	Joo KM, Jin J, Kim E, Ho Kim K, Kim Y, Gu Kang B, Kang YJ, Lathia JD, Cheong KH, Song PH, et al: MET signaling regulates glioblastoma stem cells. Cancer Res. 72:3828–3838. 2012. View Article : Google Scholar : PubMed/NCBI
24	Keith B and Simon MC: Hypoxia-inducible factors, stem cells, and cancer. Cell. 129:465–472. 2007. View Article : Google Scholar : PubMed/NCBI
25	Qiang L, Wu T, Zhang HW, Lu N, Hu R, Wang YJ, Zhao L, Chen FH, Wang XT, You QD, et al: HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. Cell Death Differ. 19:284–294. 2012. View Article : Google Scholar
26	Shi X, Zhang Y, Zheng J and Pan J: Reactive oxygen species in cancer stem cells. Antioxid Redox Signal. 16:1215–1228. 2012. View Article : Google Scholar : PubMed/NCBI
27	Ding S, Li C, Cheng N, Cui X, Xu X and Zhou G: Redox regulation in cancer stem cells. Oxid Med Cell Longev. 2015:7507982015. View Article : Google Scholar : PubMed/NCBI
28	Im CN, Yun HH, Yoo HJ, Park MJ and Lee JH: Enhancement of SOX-2 expression and ROS accumulation by culture of A172 glioblastoma cells under non-adherent culture conditions. Oncol Rep. 34:920–928. 2015. View Article : Google Scholar : PubMed/NCBI
29	Haque A, Banik NL and Ray SK: Molecular alterations in glioblastoma: Potential targets for immunotherapy. Prog Mol Biol Transl Sci. 98:187–234. 2011. View Article : Google Scholar : PubMed/NCBI
30	Ohgaki H and Kleihues P: Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 170:1445–1453. 2007. View Article : Google Scholar : PubMed/NCBI
31	Birchmeier C, Birchmeier W, Gherardi E and Vande Woude GF: Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 4:915–925. 2003. View Article : Google Scholar : PubMed/NCBI
32	Trusolino L, Bertotti A and Comoglio PM: MET signalling: Principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 11:834–848. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kong DS, Song SY, Kim DH, Joo KM, Yoo JS, Koh JS, Dong SM, Suh YL, Lee JI, Park K, et al: Prognostic significance of c-Met expression in glioblastomas. Cancer. 115:140–148. 2009. View Article : Google Scholar
34	Nabeshima K, Shimao Y, Sato S, Kataoka H, Moriyama T, Kawano H, Wakisaka S and Koono M: Expression of c-Met correlates with grade of malignancy in human astrocytic tumours: An immunohistochemical study. Histopathology. 31:436–443. 1997. View Article : Google Scholar
35	Kim B, Jung N, Lee S, Sohng JK and Jung HJ: Apigenin inhibits cancer stem cell-like phenotypes in human glioblastoma cells via suppression of c-Met signaling. Phytother Res. 30:1833–1840. 2016. View Article : Google Scholar : PubMed/NCBI
36	Jung HJ and Kwon HJ: Exploring the role of mitochondrial UQCRB in angiogenesis using small molecules. Mol Biosyst. 9:930–939. 2013. View Article : Google Scholar : PubMed/NCBI
37	Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S and Comoglio PM: Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 3:347–361. 2003. View Article : Google Scholar : PubMed/NCBI
38	Comito G, Calvani M, Giannoni E, Bianchini F, Calorini L, Torre E, Migliore C, Giordano S and Chiarugi P: HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. Free Radic Biol Med. 51:893–904. 2011. View Article : Google Scholar : PubMed/NCBI
39	Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, et al: Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 436:123–127. 2005. View Article : Google Scholar : PubMed/NCBI
40	Cannito S, Novo E, Compagnone A, Valfrè di Bonzo L, Busletta C, Zamara E, Paternostro C, Povero D, Bandino A, Bozzo F, et al: Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. Carcinogenesis. 29:2267–2278. 2008. View Article : Google Scholar : PubMed/NCBI