인간 유방암 세포주 BT-474와 MCF7에서 Bacteroides fragilis Toxin에 의한 E-cadherin 분절과 프로테아좀에 의한 분해
Bacteroides fragilis Toxin Induces Cleavage and Proteasome Degradation of E-cadherin in Human Breast Cancer Cell Lines BT-474 and MCF7
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Enterotoxigenic Bacteroides fragilis (ETBF)는 염증성 장 질환과 대장암을 유발하며 아연 의존성 metalloprotease인 B. fragilis toxin (BFT)를 분비한다. BFT는 epithelial cell의 E-cadherin을 80 kDa ectodomain과 33 kDa intracellular domain으로 분절을 유도한다. 생성된 E-cadherin intracellular domain은 순차적으로 γ-secretase에 의해 분절되어 28 kDa E-cadherin intracellular fragment은 아직까지 밝혀지지 않는 기작으로 분해된다. 본 연구에서는 BFT 유도 E-cadherin 분절로 인해 생성된 28 kDa E-cadherin intracellular fragment는 proteasome에 의해서 분해된다는 것을 확인하였다. 또한 BFT 유도 E-cadherin 분절 기작이 대장암 세포가 아닌 인간 유방암 세포주 BT-474 세포에서도 동일한 기작으로 일어남을 확인하였다. 마지막으로 staurosporine 은 인간 유방암 세포주 MCF7 세포에서 E-cadherin의 분절을 유도하고 γ-secretase에 의한 E-cadherin intracellular domain의 분절이 일어났으나 proteasome에 의한 분해는 일어나지 않았다. 이러한 결과는 ETBF가 서식하는 대장이 아닌 유방에서도 BFT에 의한 E-cadherin 분절이 일어날 수 있으며 ETBF가 대장암 이외의 다른 암에도 관여할 수 있음을 시사한다.
Abstract
Enterotoxigenic Bacteroides fragilis (ETBF) has been reported to promote colitis and colon cancer through the secretion of B. fragilis toxin (BFT), a zinc-dependent metalloprotease. In colonic epithelial cells, BFT induces the cleavage of E-cadherin into the 80 kDa ectodomain and the 33 kDa membrane-bound intracellular domain. The resulting membrane-tethered fragment is then cleaved by γ-secretase forming the 28 kDa E-cadherin intracellular fragment. The 28 kDa cytoplasmic fragment is then degraded by an unknown mechanism. In this study, we found that the 28 kDa E-cadherin intracellular fragment was degraded by the proteasome complex. In addition, we found that this sequential E-cadherin cleavage mechanism is found not only in colonic epithelial cells but also in the human breast cancer cell line, BT-474. Finally, we report that staurosporine also induces E-cadherin cleavage in the human breast cancer cell line, MCF7, through γ-secretase. However, further degradation of the 28 kDa E-cadherin intracellular domain is not dependent on the proteasome complex. These results suggest that the BFT-induced E-cadherin cleavage mechanism is conserved in both colonic and breast cancer cells. This observation indicates that ETBF may also play a role in the carcinogenesis of tissues other than the colon.
참고문헌 (38)
- Eckburg PB, "Diversity of the human intestinal microbial flora", Science, 308, pp.1635~1638 (2005)[DOI]
- Pierce JV, "Genomic diversity of enterotoxigenic strains of Bacteroides fragilis", PLoS One, 11, pp.e0158171~ (2016)[DOI]
- 황순재, "Bacteroides fragilis Toxin Induces IL-8 Secretion in HT29", C1 Cells through Disruption of E-cadherin Junctions, 2013, pp.13(5), 213~217[DOI]
- Lee CG, "Bacteroides fragilis toxin induces intestinal epithelial cell secretion of interleukin-8 by the E-cadherin", β-catenin, Biomedicines, pp.2022, 10[DOI]
- Goodwin AC, "Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis", Proc Natl Acad Sci U S A, 108, pp.15354~15359 (2011)[DOI]
- Allen J, "Epigenetic changes induced by Bacteroides fragilis toxin", Infect Immun, 87, pp.e00447~e00418 (2019)[DOI]
- Devaux CA, "The E-cadherin cleavage associated to pathogenic bacteria infections can favor bacterial invasion and transmigration, dysregulation of the immune response and cancer induction in humans", Front Microbiol, 10, pp.2598~ (2019)[DOI]
- Koirala R, "Inside-out regulation of E-cadherin conformation and adhesion", Proc Natl Acad Sci U S A, 118, pp.e2104090118~ (2021)[DOI]
- Troyanovsky SM, "Adherens junction: the ensemble of specialized cadherin clusters", Trends Cell Biol (2022)[DOI]
- Na TY, "The functional activity of E-cadherin controls tumor cell metastasis at multiple steps", Proc Natl Acad Sci U S A, 117, pp.5931~5937 (2020)[DOI]
- Damsky CH, "Identification and purification of a cell surface glycoprotein mediating intercellular adhesion in embryonic and adult tissue", Cell, 34, pp.455~466 (1983)[DOI]
- Yoo CB, "γ-Secretase-dependent cleavage of E-cadherin by staurosporine in breast cancer cells", Cell Commun Adhes, 19, pp.11~16 (2012)[DOI]
- Hugo HJ, "Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction-a model for cross-modulation", BMC Cancer, 9, pp.235~ (2009)[DOI]
- Wu S, "Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage", J Cell Sci, 120(Pt 11), pp.1944~1952 (2007)
- Rios-Doria J, "The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells", J Biol Chem, 278, pp.1372~1379 (2003)[DOI]
- Grabowska MM, "Soluble E-cadherin : more than a symptom of disease", Front Biosci(Landmark Ed), 17, pp.1948~1964 (2012)[DOI]
- Bard JAM, "Structure and function of the 26S proteasome", Annu Rev Biochem, 87, pp.697~724 (2018)[DOI]
- Rousseau A, "Regulation of proteasome assembly and activity in health and disease", Nat Rev Mol Cell Biol, 19, pp.697~712 (2018)[DOI]
- Hitchcock AL, "A subset of membrane-associated proteins is ubiquitinated in response to mutations in the endoplasmic reticulum degradation machinery", Proc Natl Acad Sci U S A, 100, pp.12735~12740 (2003)[DOI]
- Asakura T, "Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1", Int J Oncol, 46, pp.2251~2260 (2015)[DOI]
- Yang JY, "MDM2promotes cell motility and invasiveness by regulating E-cadherin degradation", Mol Cell Biol, 26, pp.7269~7282 (2006)[DOI]
- Kisselev AF, "Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate", J Biol Chem, 281, pp.8582~8590 (2006)[DOI]
- Kortuem KM, "Carfilzomib", Blood, 121, pp.893~897 (2013)[DOI]
- Quaglio AEV, "Gut microbiota, inflammatory bowel disease and colorectal cancer", World J Gastroenterol, 28, pp.4053~4060 (2022)[DOI]
- Wu S, "Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway", Infect Immun, 72, pp.5832~5839 (2004)[DOI]
- 박찬혁, "Intestinal microbiota, chronic inflammation, and colorectal cancer", Intestinal research, 16(3), pp.338~345 (2018), 대한장연구학회
- Cao Y, "Enterotoxigenic Bacteroides fragilis promotes intestinal inflammation and malignancy by inhibiting exosome-packaged miR-149-3p", Gastroenterology, 161, pp.1552~1566 (2021)[DOI]
- Hieken TJ, "The microbiome of aseptically collected human breast tissue in benign and malignant disease", Sci Rep, 6, pp.30751~ (2016)[DOI]
- Pickard JM, "Gut microbiota : role in pathogen colonization, immune responses, and inflammatory disease", Immunol Rev, 279, pp.70~89 (2017)[DOI]
- Parida S, "A procarcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates Notch and β-catenin axes", Cancer Discov, 11, pp.1138~1157 (2021)[DOI]
- Lehembre F, "NCAM-induced focal adhesion assembly : a functional switch upon loss of E-cadherin", EMBO J, 27, pp.2603~2615 (2008)[DOI]
- Pohl C, "Cellular quality control by the ubiquitin-proteasome system and autophagy", Science, 366, pp.818~822 (2019)[DOI]
- Pei J, "Targeting lysosomal degradation pathways : new strategies and techniques for drug discovery", J Med Chem, 64, pp.3493~3507 (2021)[DOI]
- Steinhusen U, "Cleavage and shedding of E-cadherin after induction of apoptosis", J Biol Chem, 276, pp.4972~4980 (2001)[DOI]
- Wu WJ, "Mechanism of E-cadherin lysosomal degradation", Nat Rev Cancer, 9, pp.143~ (2009)[DOI]
- Oerlemans R, "Molecular basis of bortezomib resistance : proteasome subunit beta5(PSMB5)gene mutation and overexpression of PSMB5 protein", Blood, 112, pp.2489~2499 (2008)[DOI]
- Wu S, "Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin", Proc Natl Acad Sci U S A, 95, pp.14979~14984 (1998)[DOI]
- Heerboth S, "EMT and tumor metastasis", Clin Transl Med, 4, pp.6~ (2015)[DOI]