A Pathway for the Control of Anoikis Sensitivity by E-Cadherin and Epithelial-to-Mesenchymal Transition

Kumar, Sanjeev; Park, Sun Hee; Cieply, Benjamin; Schupp, Jane E.; Killiam, Elizabeth; Zhang, Fan; Rimm, David L.; Frisch, Steven M.

doi:10.1128/mcb.01342-10

Cited by 120 publications

(101 citation statements)

References 104 publications

(117 reference statements)

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“…There have been studies linking CAFs to chemoresistance in prostate cancer cells (38) and to epithelial-mesenchymal transition (39), which has been linked to the inhibition of anoikis through the activity of the protein NRAGE (40). However, a direct connection between CAFs and anoikis protection has yet to be conclusively demonstrated.…”

Section: Discussionmentioning

confidence: 99%

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

Weigel¹,

Jakimenko²,

Conti³

et al. 2014

Molecular Cancer Research

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Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulinlike growth factor-binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells.

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Section: Discussionmentioning

confidence: 99%

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

Weigel¹,

Jakimenko²,

Conti³

et al. 2014

Molecular Cancer Research

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“…However, tumor cells resist anoikis partially by forming cell clusters (32,33). Notably, characteristics of EMT, including upregulation of vimentin expression and downregulation of E-cadherin expression, were found to be associated with anoikis (34,35). Meanwhile, EMT was also shown to play an important role in CTC cluster formation (21).…”

Section: Hypothesismentioning

confidence: 97%

A circulating tumor cell cluster-based model for tumor metastasis (Hypothesis)

Hong

Li²,

Zhang

2016

Oncology Letters

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Abstract. Metastasis is the major cause of mortality in patients with malignancies; however, the mechanisms of tumor cell dissemination and metastasis formation are obscure. Circulating tumor cells (CTCs) are believed to be a critical step for distant metastasis and are associated with a poor patient prognosis. The precise processes of metastasis formation from CTCs are vague. In the present study, we hypothesize that two CTC cluster-based mechanisms of tumor cell inoculation in ectopic organs may be viable: i) Formation of a micro-cancer embolus due to interception of CTC clusters by small vessels; and ii) formation of micrometastasis in an extravasation-dependent or -independent manner. Pathological evidence of micro-cancer emboli is critical for the verifications of this hypothesis. If proved true, this hypothesis will provide a novel perspective for cancer metastasis and has valuable clinical implications.

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“…28 Interestingly, NRAGE has also been suggested to act as an oncoprotein by transcriptionally inhibiting p14ARF expression via TBX2 in the nucleus. 29 Therefore, we hypothesized that the functional interplay between nuclear NRAGE and DDR by regulating RNF8 and BARD1 stability was through ULF-dependent regulation of p14ARF protein, which will be further studied in our future studies.…”

Section: Discussionmentioning

confidence: 99%

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

Yang

Pan

et al. 2016

Cell Death Differ

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NRAGE, a neurotrophin receptor-interacting melanoma antigen-encoding gene homolog, is significantly increased in the nucleus of radioresistant esophageal tumor cell lines and is highly upregulated to promote cell proliferation in esophageal carcinomas (ECs). However, whether the overexpressed NRAGE promotes cell growth by participating in DNA-damage response (DDR) is still unclear. Here we show that NRAGE is required for efficient double-strand breaks (DSBs) repair via homologous recombination repair (HRR) and downregulation of NRAGE greatly sensitizes EC cells to DNA-damaging agents both in vitro and in vivo. Moreover, NRAGE not only regulates the stability of DDR factors, RNF8 and BARD1, in a ubiquitin-proteolytic pathway, but also chaperons the interaction between BARD1 and RNF8 via their RING domains to form a novel ternary complex. Additionally, the expression of NRAGE is closely correlated with RNF8 and BARD1 in esophageal tumor tissues. In summary, our findings reveal a novel function of NRAGE that will help to guide personalized esophageal cancer treatments by targeting NRAGE to increase cell sensitivity to DNA-damaging therapeutics in the long run. In mammalian cells, DNA lesions are always endogenously and exogenously induced, 1 among which double-strand breaks (DSBs) are the most lethal lesions.2 Therefore, efficient DNA-damage response (DDR) is essential to maintain genomic integrity.1,3 However, DDR is a double-edged sword. In normal organisms, DDR protects cells from tumorigenesis, whereas in tumor cells, DDR enables cells to grow and resist DNA-damaging therapeutic agents. 4 Thus, in order to correctly use DDR factors in cancer diagnosis and targeted therapy, it is important to study molecular pathways underlying DDR in cancer cells. 5NRAGE is a member of the melanoma-associated antigen (MAGE) family. 6 Previous studies reveal that it is possibly a DDR factor: (1) upregulation of NRAGE in the nucleus is highly associated with the development of esophageal carcinoma (EC) by interacting with the proliferating cell nuclear antigen (PCNA); 7 (2) the level of NRAGE is significantly increased in the nucleus of radioresistant EC cells; 8 (3) NRAGE knockout (KO) mice exhibit depression-like behavior 9 and disorder in circadian clock, 10 both of which are analogous to DDR defective scenarios.11,12 However, to our knowledge, there has been no direct report concerning the role of NRAGE in DDR.In the present study, we aim to study the role and the underlying mechanisms of NRAGE in DDR. Our data support that NRAGE is a positive regulator in homologous recombination (HR) and regulates the chemoresistance of EC cells both in vivo and in vitro. From mechanism, it regulates the stability of RNF8 and BARD1 via the ubiquitin-proteasome pathway and interacts with the RING domains of the two proteins as a chaperon to form a novel ternary complex to participate in DDR. Furthermore, clinical characterization of NRAGE, RNF8, and BARD1 in squamous EC tissues shows that the expression of NRAGE protein is closely related wi...

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A Pathway for the Control of Anoikis Sensitivity by E-Cadherin and Epithelial-to-Mesenchymal Transition

Cited by 120 publications

References 104 publications

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis

A circulating tumor cell cluster-based model for tumor metastasis (Hypothesis)

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

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