Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of anoikis and tumorigenesis

被引:32
作者
Kamarajan, Pachiyappan [1 ]
Alhazzazi, Turki Y. [1 ]
Danciu, Theodora [1 ]
D'silva, Nisha J. [1 ,2 ]
Verdin, Eric [3 ]
Kapila, Yvonne L. [1 ]
机构
[1] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[3] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94143 USA
基金
美国国家卫生研究院;
关键词
sirtuin-3; receptor-interacting protein; anoikis resistance; tumorigenesis; oral squamous cell carcinoma; orasphere; ANCHORAGE-INDEPENDENT GROWTH; DEATH DOMAIN; CELL-DEATH; NUDE-MICE; DEACETYLASE; APOPTOSIS; HOMOLOG; LOCALIZATION; RESISTANCE; SURVIVAL;
D O I
10.1002/cncr.27655
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BACKGROUND: Regulating cross-talk between anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like cancer. Previously, the authors demonstrated that anoikis activates a signaling pathway involving the CD95/Fas-mediated signaling pathway that is regulated by receptor-interacting protein (RIP), a kinase that shuttles between Fas-mediated cell death and integrin/focal adhesion kinase (FAK)-mediated survival pathways. Because it is known that sirtuin-3 (SIRT3), a nicotinamide adenine dinucleotide-dependent deacetylase, regulates cell survival, metabolism, and tumorigenesis, the authors hypothesized that SIRT3 may engage in cross-talk with Fas/RIP/integrin/FAK survival-death pathways in cancer cell systems. METHODS: Using immunohistochemical staining, immunoblotting, human tissue microarrays, and overexpression and suppression approaches in vitro and in vivo, the roles of RIP and SIRT3 were examined in oral squamous cell carcinoma (OSCC) anoikis resistance and tumorigenesis. RESULTS: RIP and SIRT3 had opposite expression profiles in OSCC cells and tissues. Stable suppression of RIP enhanced SIRT3 levels, whereas stable suppression of SIRT3 did not impact RIP levels in OSCC cells. The authors observed that, as OSCC cells became anoikis-resistant, they formed multicellular aggregates or oraspheres in suspension conditions, and their expression of SIRT3 increased as their RIP expression decreased. Also, anoikis-resistant OSCC cells with higher SIRT3 and low RIP expression induced an increased tumor burden and incidence in mice, unlike their adherent OSCC cell counterparts. Furthermore, stable suppression of SIRT3 inhibited anoikis resistance and reduced tumor incidence. CONCLUSIONS: The current results indicted that RIP is a likely upstream, negative regulator of SIRT3 in anoikis resistance, and an anoikis-resistant orasphere phenotype defined by higher SIRT3 and low RIP expression contributes to a more aggressive phenotype in OSCC development. Cancer 2012. (c) 2012 American Cancer Society.
引用
收藏
页码:5800 / 5810
页数:11
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