Ferroportin depletes iron needed for cell cycle progression in head and neck squamous cell carcinoma

被引:7
作者
Belvin, Benjamin Ross [1 ]
Lewis, Janina P. P. [1 ,2 ,3 ]
机构
[1] Philips Inst Oral Hlth Res, Sch Dent, Richmond, VA 23298 USA
[2] Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA
[3] Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Richmond, VA 23284 USA
基金
美国国家卫生研究院;
关键词
iron; cell proliferation; ferroportin; head and neck squamous cell carcinoma; iron metabolism; senescence; Oral Epithelial Cells; RIBONUCLEOTIDE REDUCTASE; DNA-REPLICATION; GROWTH; TRANSFERRIN; CHELATORS; CANCER; OVEREXPRESSION; INHIBITION; EGFR;
D O I
10.3389/fonc.2022.1025434
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
IntroductionFerroportin (FPN), the only identified eukaryotic iron efflux channel, plays an important role in iron homeostasis and is downregulated in many cancers. To determine if iron related pathways are important for Head and Neck Squamous Cell Carcinoma (HNSCC) progression and proliferation, we utilize a model of FPN over-expression to simulate iron depletion and probe associated molecular pathways. MethodsThe state of iron related proteins and ferroptosis sensitivity was assessed in a panel of metastatic HNSCC cell lines. Stable, inducible expression of FPN was confirmed in the metastatic HNSCC lines HN12 and JHU-022 as well as the non-transformed normal oral keratinocyte (NOK) cell line and the effect of FPN mediated iron depletion was assessed in these cell lines. ResultsHNSCC cells are sensitive to iron chelation and ferroptosis, but the non-transformed NOK cell line is not. We found that FPN expression inhibits HNSCC cell proliferation and colony formation but NOK cells are unaffected. Inhibition of cell proliferation is rescued by the addition of hepcidin. Decreases in proliferation are due to the disruption of iron homeostasis via loss of labile iron caused by elevated FPN levels. This in turn protects HNSCC cells from ferroptotic cell death. Expression of FPN induces DNA damage, activates p21, and reduces levels of cyclin proteins thereby inhibiting cell cycle progression of HNSCC cells, arresting cells in the S-phase. Induction of FPN severely inhibits Edu incorporation and increased beta-galactosidase activity, indicating cells have entered senescence. Finally, in an oral orthotopic mouse xenograft model, FPN induction yields a significant decrease in tumor growth. ConclusionsOur results indicate that iron plays a role in HNSCC cell proliferation and growth and is important for cell cycle progression. Iron based interventional strategies such as ferroptosis or iron chelation may have potential therapeutic benefits in advanced HNSCC.
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页数:15
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共 44 条
[1]   MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis [J].
Alborzinia, Hamed ;
Florez, Andres F. ;
Kreth, Sina ;
Brueckner, Lena M. ;
Yildiz, Umut ;
Gartlgruber, Moritz ;
Odoni, Dorett, I ;
Poschet, Gernot ;
Garbowicz, Karolina ;
Shao, Chunxuan ;
Klein, Corinna ;
Meier, Jasmin ;
Zeisberger, Petra ;
Nadler-Holly, Michal ;
Ziehm, Matthias ;
Paul, Franziska ;
Burhenne, Juergen ;
Bell, Emma ;
Shaikhkarami, Marjan ;
Wuerth, Roberto ;
Stainczyk, Sabine A. ;
Wecht, Elisa M. ;
Kreth, Jochen ;
Buettner, Michael ;
Ishaque, Naveed ;
Schlesner, Matthias ;
Nicke, Barbara ;
Stresemann, Carlo ;
Llamazares-Prada, Maria ;
Reiling, Jan H. ;
Fischer, Matthias ;
Amit, Ido ;
Selbach, Matthias ;
Herrmann, Carl ;
Woelfl, Stefan ;
Henrich, Kai-Oliver ;
Hoefer, Thomas ;
Trumpp, Andreas ;
Westermann, Frank .
NATURE CANCER, 2022, 3 (04) :471-+
[2]   Clinical update on head and neck cancer: molecular biology and ongoing challenges [J].
Alsahafi, Elham ;
Begg, Katheryn ;
Amelio, Ivano ;
Raulf, Nina ;
Lucarelli, Philippe ;
Sauter, Thomas ;
Tavassoli, Mahvash .
CELL DEATH & DISEASE, 2019, 10 (8)
[3]   Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck [J].
Argiris, Athanassios ;
Harrington, Kevin J. ;
Tahara, Makoto ;
Schulten, Jeltje ;
Chomette, Pauline ;
Castro, Ana Ferreira ;
Licitra, Lisa .
FRONTIERS IN ONCOLOGY, 2017, 7
[4]  
Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI [10.3322/caac.21492, 10.3322/caac.21609]
[5]   TYROSINE PHOSPHORYLATION AS A MARKER FOR ABERRANTLY REGULATED GROWTH-PROMOTING PATHWAYS IN CELL-LINES DERIVED FROM HEAD AND NECK MALIGNANCIES [J].
CARDINALI, M ;
PIETRASZKIEWICZ, H ;
ENSLEY, JF ;
ROBBINS, KC .
INTERNATIONAL JOURNAL OF CANCER, 1995, 61 (01) :98-103
[6]   Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma [J].
Chan, Kin Tak ;
Choi, Mei Yuk ;
Lai, Kenneth K. Y. ;
Tan, Winnie ;
Tung, Lai Nar ;
Lam, Ho Yu ;
Tong, Daniel K. H. ;
Lee, Nikki P. ;
Law, Simon .
ONCOLOGY REPORTS, 2014, 31 (03) :1296-1304
[7]   The Iron Chelators Dp44mT and DFO Inhibit TGF-β-induced Epithelial-Mesenchymal Transition via Up-Regulation of N-Myc Downstream-regulated Gene 1 (NDRG1) [J].
Chen, Zhiqiang ;
Zhang, Daohai ;
Yue, Fei ;
Zheng, Minhua ;
Kovacevic, Zaklina ;
Richardson, Des R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (21) :17016-17028
[8]   Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth [J].
Deng, Zhiyong ;
Manz, David H. ;
Torti, Suzy V. ;
Torti, Frank M. .
ONCOTARGET, 2017, 8 (47) :82231-82243
[9]   The Hallmarks of Ferroptosis [J].
Dixon, Scott J. ;
Stockwell, Brent R. .
ANNUAL REVIEW OF CANCER BIOLOGY, VOL 3, 2019, 3 :35-54
[10]   Ironing out Ferroportin [J].
Drakesmith, Hal ;
Nemeth, Elizabeta ;
Ganz, Tomas .
CELL METABOLISM, 2015, 22 (05) :777-787