Constitutive expression of SOCS3 confers resistance to IFN-α in chronic myelogenous leukemia cells

Sakai, Ikuya; Takeuchi, Kazuto; Yamauchi, Hayato; Narumi, Hiroshi; Fujita, Shigeru

doi:10.1182/blood-2002-01-0073

Cited by 92 publications

(68 citation statements)

References 37 publications

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“…Loss of SOCS3 function results in elevated STAT5 activation leading to higher metastasis in colorectal carcinoma patients [89]. SOCS3 expression is elevated in chronic myeloid leukemia (CML) and confers resistance to interferon α (IFNα) treatment [90] indicating that expression of SOCS3 is associated with disease progression.…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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“…In support, three IFN-insensitive WM 1158R, WM 9 and 1205 Lu melanoma lines had high basal expression of SOCS 3 compared to sensitive cells. Furthermore, breast cancer (Evans et al, 2007) and leukaemia cells (Sakai et al, 2002) showed elevated constitutive expression of SOCS 1 and SOCS 3 and the resistance to proinflammatory cytokines including IFN-g. Perhaps IFN sensitivity of a SOCS 3 promoter is reduced due to aberrant expression of an activatory transcription factor(s). In this context, aberrant activation of tissue-specific promoters has been observed in cancers (Kovarik et al, 1993).…”

Section: Expression Profiles Of Socss In Melanoma Cellsmentioning

confidence: 99%

“…These studies indicated that aberrant silencing could be a cause for constitutive activation of JAK/STAT pathway in cancer cells. However, other studies also indicated that malignant cells compared to their normal counterparts express SOCS genes constitutively (Sakai et al, 2002;Li et al, 2004;Evans et al, 2007) and forced expression of SOCS transgene often conferred resistance to IFN. Constitutive expression can potentially hamper immunotherapy by inactivating cytokine signals.…”

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confidence: 99%

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

et al. 2007

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The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the evolution of an IFN-resistant state in vitro using melanoma cell lines. We found that the cells became less sensitive to antiproliferative effect of IFN-g after prolonged cultivation enabling us to isolate sensitive and resistant subclones of the parental line. We investigated transcription of signal transducer and activator of transcription (STAT) 1 -6 and suppressor of cytokine signalling (SOCS) 1 -3 genes, and phosphorylation of STAT 1 protein. The resistant subline (termed WM 1158R) differed from the sensitive subline (WM 1158S) by a constitutive expression of SOCS 3, lack or weak SOCS 1 -3 activation following IFN-g, and short duration of cytokine activatory signal. Similar correlations were observed in additional melanoma lines differing in IFN sensitivities. At the protein level, IFN-g induced strong and prolonged STAT 1 activation at serine 727 (S727) in WM 1158R while in WM 1158S cells phosphorylation of this amino acid was much less pronounced. On the other hand, phosphorylation of tyrosine 701 (Y701) was stimulated regardless of the sensitivity phenotype. In conclusion, constitutive expression of SOCS 3 is correlated with attenuation of its induction following IFN treatment. These results suggest that progression of melanoma cells from IFN sensitivity to IFN insensitivity associates with changes in SOCS expression.

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“…Persistent expression of SOCS1 and/or SOCS3 is observed in several haematological malignancies. Such as cutaneous T cell lymphoma, chronic myeloid leukemia, ALK+ anaplastic large cell lymphoma and some acute leukemia (Schuringa et al, 2000;Brender et al, 2001;Sakai et al, 2002;Cho-Vega et al, 2004;Roman-Gomaz et al, 2004). Also, in patients with colorectal cancer, papillary thyroid cancer, glioblastoma primary tissues, breast cancer and hepatocellular carcinoma tumors protein expression of SOCS1 and SOCS3 (Sasi et al, 2010;Wu et al, 2011;Ayyildiz et al, 2014;Kobawala et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of SOCS1 and SOCS3 in Patients with Oral Squamous Cell Carcinoma

Trivedi¹,

Kobawala²,

Ghosh³

et al. 2017

AJCRCO

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Though Suppressors of Cytokine Signaling (SOCS) proteins are known for negative feedback regulators of cytokine signaling their role in cancer is controversial. In the current study we sought to explore the occurrence of SOCS1 and SOCS3 in oral squamous cell carcinoma (OSCC) patients and evaluate their potential relationship with clinicopathological parameters and disease outcome. Using immunohistochemistry protein expression of SOCS1 and SOCS3 were evaluated from paraffin embedded primary OSCC tumors of 61 patients. Scoring was done by semiquantitative method. Cytoplasmic expression of SOCS1 and SOCS3 was noted in 54% and 59% of OSCC patients, respectively. Overexpression of SOCS1 was found to be significantly correlated with nodal status (p=0.020), disease stage (P = 0.014), histological grade (p=0.032) and lymphatic permeation (p=0.0001). SOCS3 showed significant association with nodal status (p=0.011), disease stage (p =0.009), lymphatic (p=0.0001) and vascular permeation (p=0.002). Kaplan-Meier curves for relapse-free survival (RFS) and overall survival (OS) demonstrated that SOCS3 remained significant indicator for predicting reduced RFS (Log rank=6.21, p=0.0127) and worse OS (Log rank=4.49, p=0.0340) for OSCC patients. However, in multivariate analysis it failed to reach at statistically significant. Our study found upregulated protein expression of SOCS1 and SOCS3 in advanced stage of OSCC patients having aggressive tumor phenotype. Therefore, study of SOCS1 and SOCS3 might be useful for precisely identifying high risk OSCC patients for more effective tailored treatment.

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Constitutive expression of SOCS3 confers resistance to IFN-α in chronic myelogenous leukemia cells

Cited by 92 publications

References 37 publications

SOCS proteins in regulation of receptor tyrosine kinase signaling

SOCS proteins in regulation of receptor tyrosine kinase signaling

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

Clinical Relevance of SOCS1 and SOCS3 in Patients with Oral Squamous Cell Carcinoma

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