Quercetin-induced autophagy flux enhances TRAIL-mediated tumor cell death

Moon,Ji-Hong; Eo,Seong  Kug; Lee,John  Hwa; Park,Sang-Youel

doi:10.3892/or.2015.3991

Quercetin-induced autophagy flux enhances TRAIL-mediated tumor cell death

Authors:
- Ji-Hong Moon
- Seong Kug Eo
- John Hwa Lee
- Sang-Youel Park
View Affiliations

Affiliations: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea
Published online on: May 19, 2015 https://doi.org/10.3892/or.2015.3991
Pages: 375-381

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

Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. We investigated whether quercetin enhances TRAIL-induced tumor cell death and the possible mechanism in human lung cancer cells. We identified that quercetin markedly enhanced TRAIL-mediated lung cancer cell death. Quercetin treatment dose-dependently decreased the p62 protein expression and increased GFP-LC3B. Autophagy flux inhibitor, chloroquine treatment blocked the enhancing effects of TRAIL-induced apoptosis by quercetin. Our results indicated that quercetin enhanced TRAIL-induced cell death via autophagy flux activation, and also suggest that quercetin may be a therapeutic agent against human lung cancer via combination therapy with many anticancer drugs including TRAIL.

View Figures

View References

1	Baowen Q, Yulin Z, Xin W, Wenjing X, Hao Z, Zhizhi C, Xingmei D, Xia Z, Yuquan W and Lijuan C: A further investigation concerning correlation between anti-fibrotic effect of liposomal quercetin and inflammatory cytokines in pulmonary fibrosis. Eur J Pharmacol. 642:134–139. 2010. View Article : Google Scholar : PubMed/NCBI
2	Boots AW, Haenen GR and Bast A: Health effects of quercetin: From antioxidant to nutraceutical. Eur J Pharmacol. 585:325–337. 2008. View Article : Google Scholar : PubMed/NCBI
3	Qu L, Liang X, Gu B and Liu W: Quercetin alleviates high glucose-induced Schwann cell damage by autophagy. Neural Regen Res. 9:1195–1203. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kim H, Moon JY, Ahn KS and Cho SK: Quercetin induces mitochondrial mediated apoptosis and protective autophagy in human glioblastoma U373MG cells. Oxid Med Cell Longev. 2013:5964962013.
5	Wei L, Liu JJ, Cao J, Du NC, Ji LN and Yang XL: Role of autophagy in quercetin-induced apoptosis in human bladder carcinoma BIU-87 cells. Zhonghua Zhong Liu Za Zhi. 34:414–418. 2012.In Chinese. PubMed/NCBI
6	Wei YQ, Zhao X, Kariya Y, Fukata H, Teshigawara K and Uchida A: Induction of apoptosis by quercetin: Involvement of heat shock protein. Cancer Res. 54:4952–4957. 1994.PubMed/NCBI
7	Murakami A, Ashida H and Terao J: Multitargeted cancer prevention by quercetin. Cancer Lett. 269:315–325. 2008. View Article : Google Scholar : PubMed/NCBI
8	Steller H: Mechanisms and genes of cellular suicide. Science. 267:1445–1449. 1995. View Article : Google Scholar : PubMed/NCBI
9	Hickman JA: Apoptosis induced by anticancer drugs. Cancer Metastasis Rev. 11:121–139. 1992. View Article : Google Scholar : PubMed/NCBI
10	Zhang JY: Apoptosis-based anticancer drugs. Nat Rev Drug Discov. 1:101–102. 2002. View Article : Google Scholar : PubMed/NCBI
11	MacFarlane M: TRAIL-induced signalling and apoptosis. Toxicol Lett. 139:89–97. 2003. View Article : Google Scholar : PubMed/NCBI
12	Wang CW and Klionsky DJ: The molecular mechanism of autophagy. Mol Med. 9:65–76. 2003.PubMed/NCBI
13	Chen N and Karantza V: Autophagy as a therapeutic target in cancer. Cancer Biol Ther. 11:157–168. 2011. View Article : Google Scholar : PubMed/NCBI
14	Cuervo AM: Autophagy: In sickness and in health. Trends Cell Biol. 14:70–77. 2004. View Article : Google Scholar : PubMed/NCBI
15	Seglen PO, Berg TO, Blankson H, Fengsrud M, Holen I and Strømhaug PE: Structural aspects of autophagy. Adv Exp Med Biol. 389:103–111. 1996. View Article : Google Scholar : PubMed/NCBI
16	Mortimore GE, Miotto G, Venerando R and Kadowaki M: Autophagy. Subcell Biochem. 27:93–135. 1996. View Article : Google Scholar : PubMed/NCBI
17	Cuervo AM: Autophagy: Many paths to the same end. Mol Cell Biochem. 263:55–72. 2004. View Article : Google Scholar : PubMed/NCBI
18	Liu B, Bao JK, Yang JM and Cheng Y: Targeting autophagic pathways for cancer drug discovery. Chin J Cancer. 32:113–120. 2013. View Article : Google Scholar :
19	Klionsky DJ: Autophagy: From phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 8:931–937. 2007. View Article : Google Scholar : PubMed/NCBI
20	Rubinsztein DC, Cuervo AM, Ravikumar B, Sarkar S, Korolchuk V, Kaushik S and Klionsky DJ: In search of an ‘autophagomometer’. Autophagy. 5:585–589. 2009. View Article : Google Scholar : PubMed/NCBI
21	Sahani MH, Itakura E and Mizushima N: Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids. Autophagy. 10:431–441. 2014. View Article : Google Scholar : PubMed/NCBI
22	Myeku N and Figueiredo-Pereira ME: Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: Association with sequestosome 1/p62. J Biol Chem. 286:22426–22440. 2011. View Article : Google Scholar : PubMed/NCBI
23	Bartlett BJ, Isakson P, Lewerenz J, Sanchez H, Kotzebue RW, Cumming RC, Harris GL, Nezis IP, Schubert DR, Simonsen A, et al: p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. Autophagy. 7:572–583. 2011. View Article : Google Scholar : PubMed/NCBI
24	Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al: Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8:445–544. 2012. View Article : Google Scholar : PubMed/NCBI
25	Liu B, Cheng Y, Liu Q, Bao JK and Yang JM: Autophagic pathways as new targets for cancer drug development. Acta Pharmacol Sin. 31:1154–1164. 2010. View Article : Google Scholar : PubMed/NCBI
26	Jiang L, Hao JL, Jin ML, Zhang YG and Wei P: Effect of embelin on TRAIL receptor 2 mAb-induced apoptosis of TRAIL-resistant A549 non-small cell lung cancer cells. Asian Pac J Cancer Prev. 14:6115–6120. 2013. View Article : Google Scholar : PubMed/NCBI
27	Chaudhari AA, Seol JW, Lee YJ, Seol DW and Park SY: Hypoxia protects articular chondrocytes from thapsigargin-induced apoptosis. Biochem Biophys Res Commun. 381:513–517. 2009. View Article : Google Scholar : PubMed/NCBI
28	Seo JS, Moon MH, Jeong JK, Seol JW, Lee YJ, Park BH and Park SY: SIRT1, a histone deacetylase, regulates prion protein-induced neuronal cell death. Neurobiol Aging. 33:1110–1120. 2012. View Article : Google Scholar
29	Agarwal E, Brattain MG and Chowdhury S: Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal. 25:1711–1719. 2013. View Article : Google Scholar : PubMed/NCBI
30	Degterev A, Boyce M and Yuan J: A decade of caspases. Oncogene. 22:8543–8567. 2003. View Article : Google Scholar : PubMed/NCBI
31	Kroemer G and Jäättelä M: Lysosomes and autophagy in cell death control. Nat Rev Cancer. 5:886–897. 2005. View Article : Google Scholar : PubMed/NCBI
32	Boya P, González-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Métivier D, Meley D, Souquere S, Yoshimori T, et al: Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 25:1025–1040. 2005. View Article : Google Scholar : PubMed/NCBI
33	Matsumoto G, Wada K, Okuno M, Kurosawa M and Nukina N: Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell. 44:279–289. 2011. View Article : Google Scholar : PubMed/NCBI
34	Jeong JH, An JY, Kwon YT, Rhee JG and Lee YJ: Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 106:73–82. 2009. View Article : Google Scholar :
35	Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD and Levine B: Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 122:927–939. 2005. View Article : Google Scholar : PubMed/NCBI
36	Yang Z and Klionsky DJ: An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol. 335:1–32. 2009.PubMed/NCBI
37	White E and DiPaola RS: The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 15:5308–5316. 2009. View Article : Google Scholar : PubMed/NCBI
38	Wang K, Liu R, Li J, Mao J, Lei Y, Wu J, Zeng J, Zhang T, Wu H, Chen L, et al: Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy. 7:966–978. 2011. View Article : Google Scholar : PubMed/NCBI
39	Singh K, Sharma A, Mir MC, Drazba JA, Heston WD, Magi-Galluzzi C, Hansel D, Rubin BP, Klein EA and Almasan A: Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin). Mol Cancer. 13:702014. View Article : Google Scholar : PubMed/NCBI
40	Park KJ, Lee SH, Kim TI, Lee HW, Lee CH, Kim EH, Jang JY, Choi KS, Kwon MH and Kim YS: A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells. Cancer Res. 67:7327–7334. 2007. View Article : Google Scholar : PubMed/NCBI
41	Shankar E, Sivaprasad U and Basu A: Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53. Oncogene. 27:3957–3966. 2008. View Article : Google Scholar : PubMed/NCBI
42	Zauli G, Sancilio S, Cataldi A, Sabatini N, Bosco D and Di Pietro R: PI-3K/Akt and NF-kappaB/IkappaBalpha pathways are activated in Jurkat T cells in response to TRAIL treatment. J Cell Physiol. 202:900–911. 2005. View Article : Google Scholar
43	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI