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Autophagic flux is essential for the downregulation of D-dopachrome tautomerase by atractylenolide I to ameliorate intestinal adenoma formation

Journal of Cell Communication and Signaling Aims and scope

Abstract

Colorectal cancer is generally believed to progress through an adenoma - carcinoma sequence. Adenomatous polyposis coli (APC) mutations serve as the initiating event in adenoma formation. The ApcMin/+ mouse harbors a mutation in the APC gene, which is similar or identical to the mutation found in individuals with familial adenomatous polyposis and 70% of all sporadic CRC cases. Autophagy is a constitutive process required for proper cellular homeostasis. However, its role in intestinal adenoma formation is still controversial. Atractylenolide I (AT1) is a sesquiterpenoid that possesses various clinically relevant properties such as anti-tumor and anti-inflammatory activities. The role of AT1 on adenoma formation was tested in ApcMin/+ mice and its underlying mechanism in regulating autophagy was documented. D-dopachrome tautomerase (D-DT) was identified as a potential target of AT1 by an proteomics-based approach. The effects of p53 modification on autophgic flux was monitored in p53−/− and p53+/+ HCT116 cells. Small interfering RNA was used to investigate the function of Atg7 and D-DT on autophagy programme induce by AT1. AT1 effectively reduced the formation of adenoma and downregulated the tumorigenic proteins in ApcMin/+ mice. Importantly, AT1 stimulated autophagic flux through downregulating acetylation of p53. Activation of Sirt1 by AT1 was essential for the deacetylation of p53 and downregulation of D-DT. The lowered expression of COX-2 and β-catenin by AT1 were partly recovered by Atg7 knockdown. AT1 activates autophagy machinery to downregulate D-DT and reduce intestinal adenoma formation. This discovery provides evidence in vivo and in vitro that inducing autophagy by natural products maybe a potential therapy to ameliorate colorectal adenoma formation.

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Fig. 1: Atractylenolide I reduces adenoma formation
Fig. 2: Proteomic identification of D-DT as a potential target of AT1
Fig. 3: Atractylenolide I induces autophagic flux
Fig. 4: AT1 induces Sirt1 and deacetylates p53
Fig. 5: Autophagy induced downregulation of D-DT is at least partially reponsible for the regulation of adenoma formation by AT1
Fig. 6: AT1 downregulates D-DT by inducing autophagosome formation

References

  • Brock SE, Rendon BE, Yaddanapudi K et al (2012) Negative regulation of AMP-activated protein kinase (AMPK) activity by macrophage migration inhibitory factor (MIF) family members in non-small cell lung carcinomas[J]. J Biol Chem 287(45):37917–37925

    Article  CAS  Google Scholar 

  • Brock SE, Rendon BE, Xin D et al (2014) MIF family members cooperatively inhibit p53 expression and activity[J]. PLoS One 9(6):e99795

    Article  Google Scholar 

  • Chang C, Su H, Zhang D et al (2015) AMPK-dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for autophagy upon glucose starvation[J]. Mol Cell 60(6):930–940

    Article  CAS  Google Scholar 

  • Chang WL, Jackson C, Riel S et al (2017) Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas[J]. Gut

  • Chen B, Zeng C, Ye Y, Wu D, Mu Z, Liu J, Xie Y, Wu H (2017) Promoter methylation of TCF21 may repress autophagy in the progression of lung cancer. J Cell Commun Signal. https://doi.org/10.1007/s12079-017-0418-2

    Article  Google Scholar 

  • Chunhua L, Donglan L, Xiuqiong F et al (2013) Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT[J]. J Nutr Biochem 24(10):1766–1775

    Article  Google Scholar 

  • Coleman AM, Rendon BE, Zhao M et al (2008) Cooperative regulation of non-small cell lung carcinoma angiogenic potential by macrophage migration inhibitory factor and its homolog, D-dopachrome tautomerase[J]. J Immunol 181(4):2330–2337

    Article  CAS  Google Scholar 

  • Contreras AU, Mebratu Y, Delgado M et al (2013) Deacetylation of p53 induces autophagy by suppressing Bmf expression[J]. J Cell Biol 201(3):427–437

    Article  CAS  Google Scholar 

  • Cruz VH, Brekken RA (2017) Assessment of TANK-binding kinase 1 as a therapeutic target in cancer[J]. J Cell Commun Signal

  • Gewirtz DA (2016) The challenge of developing autophagy inhibition as a therapeutic strategy[J]. Cancer Res 76(19):5610–5614

    Article  CAS  Google Scholar 

  • Green DR, Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53[J]. Nature 458(7242):1127–1130

    Article  CAS  Google Scholar 

  • Guo D, Guo J, Yao J et al (2016) D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth[J]. Int J Cancer 139(9):2056–2067

    Article  CAS  Google Scholar 

  • Huang JM, Zhang GN, Shi Y et al (2014) Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway[J]. Sci Rep 4:3840

    Article  Google Scholar 

  • Jarauta V, Jaime P, Gonzalo O et al (2016) Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo[J]. Cancer Lett 382(1):1–10

    Article  CAS  Google Scholar 

  • Kim EJ, Kho JH, Kang MR et al (2007) Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity[J]. Mol Cell 28(2):277–290

    Article  CAS  Google Scholar 

  • Korinek V, Barker N, Morin PJ et al (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma[J]. Science 275(5307):1784–1787

    Article  CAS  Google Scholar 

  • Lee JP, Foote A, Fan H et al (2016) Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages[J]. Autophagy 12(6):907–916

    Article  CAS  Google Scholar 

  • Li X, Wang Y, Xiong Y et al (2016) Galangin induces autophagy via deacetylation of LC3 by SIRT1 in HepG2 cells[J]. Sci Rep 6:30496

    Article  CAS  Google Scholar 

  • Lin X, Xu W, Shao M et al (2015) Shenling Baizhu San supresses colitis associated colorectal cancer through inhibition of epithelial-mesenchymal transition and myeloid-derived suppressor infiltration[J]. BMC Complement Altern Med 15:126

    Article  Google Scholar 

  • Liu H, Zhu Y, Zhang T et al (2013) Anti-tumor effects of atractylenolide I isolated from Atractylodes macrocephala in human lung carcinoma cell lines[J]. Molecules 18(11):13357–13368

    Article  CAS  Google Scholar 

  • Merk M, Mitchell RA, Endres S et al (2012) D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family[J]. Cytokine 59(1):10–17

    Article  CAS  Google Scholar 

  • Nishiumi S, Fujishima Y, Inoue J et al (2012) Autophagy in the intestinal epithelium is not involved in the pathogenesis of intestinal tumors[J]. Biochem Biophys Res Commun 421(4):768–772

    Article  CAS  Google Scholar 

  • Ou X, Lee MR, Huang X et al (2014) SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress[J]. Stem Cells 32(5):1183–1194

    Article  CAS  Google Scholar 

  • Pasupuleti V, Du W, Gupta Y et al (2014) Dysregulated D-dopachrome tautomerase, a hypoxia-inducible factor-dependent gene, cooperates with macrophage migration inhibitory factor in renal tumorigenesis[J]. J Biol Chem 289(6):3713–3723

    Article  CAS  Google Scholar 

  • Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis[J]. Nature 359(6392):235–237

    Article  CAS  Google Scholar 

  • Ranjan A, Iwakuma T (2016) Non-canonical cell death induced by p53[J]. Int J Mol Sci 17:12

    Article  Google Scholar 

  • Rioux JD, Xavier RJ, Taylor KD et al (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis[J]. Nat Genet 39(5):596–604

    Article  CAS  Google Scholar 

  • Saitoh T, Fujita N, Jang MH et al (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production[J]. Nature 456(7219):264–268

    Article  CAS  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017[J]. CA Cancer J Clin 67(1):7–30

    Article  Google Scholar 

  • Sun X, Liang J, Yao X et al (2015) The activation of EGFR promotes myocardial tumor necrosis factor-alpha production and cardiac failure in endotoxemia[J]. Oncotarget 6(34):35478–35495

    PubMed  PubMed Central  Google Scholar 

  • Sun XG, Lin XC, Diao JX et al (2016) Pi (Spleen)-deficiency syndrome in tumor microenvironment is the pivotal pathogenesis of colorectal cancer immune escape[J]. Chin J Integr Med 22(10):789–794

    Article  CAS  Google Scholar 

  • Wang L, Wang Y, Lu Y et al (2015) Heterozygous deletion of ATG5 in Apc(Min/+) mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma[J]. Cancer Biol Ther 16(3):383–391

    Article  CAS  Google Scholar 

  • Wang P, Zhu L, Sun D, Gan F, Gao S, Yin Y, Chen L (2017) Natural products as modulator of autophagy with potential clinical prospects[J]. Apoptosis 22(3):325–356

    Article  Google Scholar 

  • Xin D, Rendon BE, Zhao M et al (2010) The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through beta-catenin-dependent and -independent mechanisms[J]. Mol Cancer Res 8(12):1601–1609

    Article  CAS  Google Scholar 

  • Xu W, Jing L, Wang Q et al (2015) Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution[J]. Oncotarget 6(30):30017–30034

    Article  Google Scholar 

  • Yu R, Yu BX, Chen JF et al (2016) Anti-tumor effects of atractylenolide I on bladder cancer cells[J]. J Exp Clin Cancer Res 35:40

    Article  Google Scholar 

Download references

Funding

Founed by the National Science Foundation of China (81573848, 81774172, 81472315), Guangdong Natural Science Foundation (2014A030313323), Planned Science Technology Project of Guangzhou (201607010146), Guangdong Province Bureau of Traditional Chinese Medicine Scientific Research Project (No: 20151024, 20161161).

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Author notes

  1. Lu Li, Linlin Jing and Junjiang Wang contributed equally to this work.

Authors and Affiliations

  1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China

    Lu Li, Xianling Gong, Ye Ma & Xuegang Sun

  2. TCM Integrated Hospital of Southern Medical University, Guangzhou, 510315, China

    Linlin Jing, Yiye Zhao & Xuegang Sun

  3. Department of Gastrointestinal Surgery, Guangdong General Hospital, Guangzhou, 510120, China

    Junjiang Wang & Xueqing Yao

  4. School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, 256600, China

    Wenjuan Xu

  5. School of Pharmacy, Guangdong Medical Universiy, Dongguan, Guangdong, 523808, China

    Xianling Gong

Authors
  1. Lu Li
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  2. Linlin Jing
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  3. Junjiang Wang
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  7. Ye Ma
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  9. Xuegang Sun
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Contributions

LL carried out the experiments; LJ, JZ, WX and XG helped to carried out the experiments; YZ and YM carried out statistical analyzes; XY helped in designing few experiments; XG designed the experiment and wrote the manuscript; All the authors reviewed the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xuegang Sun.

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All procedures involving laboratory animals were consented by the Instituted Animal Care and Use Committee of Southern Medical University.

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Not Applicable.

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All authors declare that they have no competing interests.

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Li, L., Jing, L., Wang, J. et al. Autophagic flux is essential for the downregulation of D-dopachrome tautomerase by atractylenolide I to ameliorate intestinal adenoma formation. J. Cell Commun. Signal. 12, 689–698 (2018). https://doi.org/10.1007/s12079-018-0454-6

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  • DOI: https://doi.org/10.1007/s12079-018-0454-6

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