Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

Ren,Biqiong; Luo,Shudi; Tian,Xuefei; Jiang,Zhichao; Zou,Guoying; Xu,Fei; Yin,Tieqiu; Huang,Yiran; Liu,Junlong

doi:10.3892/or.2018.6485

Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

Authors:
- Biqiong Ren
- Shudi Luo
- Xuefei Tian
- Zhichao Jiang
- Guoying Zou
- Fei Xu
- Tieqiu Yin
- Yiran Huang
- Junlong Liu
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Affiliations: Clinical Laboratory of The Second People's Hospital of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan 410007, P.R. China
Published online on: June 11, 2018 https://doi.org/10.3892/or.2018.6485
Pages: 895-901

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Abstract

Curcumin has been revealed to inhibit liver cancer, however, no studies have reported that the mechanism of curcumin's action on liver cancer is related to damage-associated molecular pattern (DAMP) molecules heat shock protein 70 (HSP70) and the toll-like receptor 4 (TLR4) signaling. This study aimed to investigate whether the activation of TLR4 signaling by HSP70 could be inhibited by curcumin, thus investigating the possible mechanism of curcumin in the inhibition of liver cancer. Western blotting was used to evaluate the expression of the HSP70 and TLR4 in HepG2 cells and ELISA was used to detect the concentration of HSP70 in cell culture medium. A thermal tolerance HepG2 (HepG2TT) cell model was established to simulate HSP70 accumulation in the microenvironment. A certain concentration of curcumin was co-cultured with HepG2 and HepG2TT cells to observe the changes of HSP70 and TLR4. Our results revealed that heat stress significantly increased the expression of extracellular HSP70 (eHSP70) and TLR4 (P<0.01), but significantly reduced the expression of intracellular HSP70 (P<0.01). Curcumin inhibited proliferation, invasion, and metastasis of HepG2 cells, caused cells to remain in the DNA S phase, promoted apoptosis, and significantly reduced intracellular HSP70, eHSP70 and TLR4 levels of HepG2TT cells. Following the removal of curcumin, eHSP70 increased again. In summary, our results demonstrated that the antitumor effect of curcumin was related to the inhibition HSP70-TLR4 signaling.

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1	Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glöckner-Pagel J, Canny S, Du K, Lukacs GL and Caplan MJ: Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science. 304:600–602. 2004. View Article : Google Scholar : PubMed/NCBI
2	Zeitlin P: Can curcumin cure cystic fibrosis? N Engl J Med. 351:606–608. 2004. View Article : Google Scholar : PubMed/NCBI
3	Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 441:431–436. 2006. View Article : Google Scholar : PubMed/NCBI
4	Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E and Ben-Neriah Y: NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 431:461–466. 2004. View Article : Google Scholar : PubMed/NCBI
5	Wheeler DS, Chase MA, Senft AP, Poynter SE, Wong HR and Page K: Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4. Respir Res. 10:312009. View Article : Google Scholar : PubMed/NCBI
6	Polly Matzinger P: Tolerance, danger, and the extended family. Annu Rev lmmunol. 12:991–1045. 1994. View Article : Google Scholar
7	Huang J, Xie Y, Sun X, Zeh HJ III, Kang R, Lotze MT and Tang D: DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’. Ageing Res Rev. 24A:3–16. 2015. View Article : Google Scholar
8	Nefla M, Holzinger D, Berenbaum F and Jacques C: The danger from within: Alarmins in arthritis. Nat Rev Rheumatol. 12:669–683. 2016. View Article : Google Scholar : PubMed/NCBI
9	Pécheur EI: Curcumin against hepatitis C virus infection: Spicing up antiviral therapies with ‘nutraceuticals’? Gut. 63:1035–1037. 2014. View Article : Google Scholar : PubMed/NCBI
10	Adewoye AH and McMahon L: Chaperones and disease. N Engl J Med. 353:2821–2822; author reply 2821–2822. 2005. View Article : Google Scholar : PubMed/NCBI
11	Land WG: Role of heat shock protein 70 in innate alloimmunity. Front Immunol. 2:892012. View Article : Google Scholar : PubMed/NCBI
12	Li G, Tang D and Lotze MT: Ménage à Trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol. 23:380–390. 2013. View Article : Google Scholar : PubMed/NCBI
13	Brusa D, Migliore E, Garetto S, Simone M and Matera L: Immunogenicity of 56°C and UVC-treated prostate cancer is associated with release of HSP70 and HMGB1 from necrotic cells. Prostate. 69:1343–1352. 2009. View Article : Google Scholar : PubMed/NCBI
14	López-Terrada D, Cheung SW, Finegold MJ and Knowles BB: Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40:1512–1515. 2009. View Article : Google Scholar
15	Baker M: Deceptive curcumin offers cautionary tale for chemists. Nature. 541:144–145. 2017. View Article : Google Scholar : PubMed/NCBI
16	Heger M: Drug screening: Don't discount all curcumin trial data. Nature. 543:402017. View Article : Google Scholar : PubMed/NCBI
17	Rozenberg P, Kocsis J, Saar M, Prohászka Z, Füst G and Fishelson Z: Elevated levels of mitochondrial mortalin and cytosolic HSP70 in blood as risk factors in patients with colorectal cancer. Int J Cancer. 133:514–518. 2013. View Article : Google Scholar : PubMed/NCBI
18	Gehrmann M, Cervello M, Montalto G, Cappello F, Gulino A, Knape C, Specht HM and Multhoff G: Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Front Immunol. 5:3072014. View Article : Google Scholar : PubMed/NCBI
19	Ren B, Luo S, Xu F, Zou G, Xu G, He J, Huang Y, Zhu H and Li Y: The expression of DAMP proteins HSP70 and cancer-testis antigen SPAG9 in peripheral blood of patients with HCC and lung cancer. Cell Stress Chaperones. 22:237–244. 2017. View Article : Google Scholar : PubMed/NCBI
20	Timmermans K, Kox M, Vaneker M, van den Berg M, John A, van Laarhoven A, van der Hoeven H, Scheffer GJ and Pickkers P: Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med. 42:551–561. 2016. View Article : Google Scholar : PubMed/NCBI
21	Camp SM, Ceco E, Evenoski CL, Danilov SM, Zhou T, Chiang ET, Moreno-Vinasco L, Mapes B, Zhao J, Gursoy G, et al: Unique toll-like receptor 4 activation by NAMPT/PBEF induces NFκB signaling and inflammatory lung injury. Sci Rep. 5:131352015. View Article : Google Scholar : PubMed/NCBI
22	Marquardt JU, Gomez-Quiroz L, Arreguin Camacho LO, Pinna F, Lee YH, Kitade M, Domínguez MP, Castven D, Breuhahn K, Conner EA, et al: Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol. 63:661–669. 2015. View Article : Google Scholar : PubMed/NCBI
23	Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, Liu H, Tian L, Fang X, Meng X, et al: Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 57:1847–1857. 2013. View Article : Google Scholar : PubMed/NCBI
24	Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, Chang SS, Lin WC, Hsu JM, Hsu YH, et al: Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell. 30:925–939. 2016. View Article : Google Scholar : PubMed/NCBI