SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

Iglesias-Gato, Diego; Chuan, Yin Choy; Wikström, Pernilla; Augsten, Sandra; Jiang, Ning; Niu, Yuanjie; Seipel, Amanda H.; Danneman, Daniela; Vermeij, Marcel; Fernández-Pérez, Leandro; Jenster, Guido; Egevad, Lars; Norstedt, Gunnar; Flores‐Morales, Amilcar

doi:10.1093/carcin/bgt304

Cited by 44 publications

(29 citation statements)

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“…Loss of SOCS2 and SOCS6 expression in hepatocellular carcinoma correlated with aggressive tumor progression and poor prognosis [85], and similar effects are seen in the case of SOCS2 and prostate cancer or breast cancer [77,86,87]. Methylation-mediated down-regulation of SOCS3 has been shown to be related to the abnormal cell growth and migration in same disease, which is mediated through loss of regulation of JAK/STAT and FAK signaling [88].…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 81%

“…Given the ability of SOCS proteins to modulate RTK signaling, transcriptional regulation of SOCS genes can provide a means of cross-talk between RTKs and other signaling pathways. It was recently demonstrated that SOCS2 expression is induced by androgens in prostate cancer cells which in turns down-regulates Src tyrosine kinase, a key mediator of RTK signaling [22]. Epigenetic silencing by DNA methylation is another layer of regulatory control of SOCS gene expression that may be of relevance for their biological actions.…”

Section: Socs Proteins In Rtk Regulationmentioning

confidence: 99%

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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: 81%

Section: Socs Proteins In Rtk Regulationmentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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“…The role of SOCS2 in cancer has been controversial (52)(53)(54)(55). In prostate cancer, it was reported that SOCS2 protein levels are reduced in CRPC and that SOCS2 inhibits the oncogenic events caused by growth hormone, such as cell proliferation and invasion (56). In contrast, another report revealed that SOCS2 protein expression was increased in prostate tumor tissues compared with benign tissues and that SOCS2 has a growth-promoting role in vitro and in vivo (57).…”

Section: Discussionmentioning

confidence: 99%

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

Misawa

Takayama

Urano

et al. 2016

Journal of Biological Chemistry

135

108

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Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e. long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10. These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.

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“…Disruption of GHR-STAT5-SOCS2 signaling pathway is also associated with metabolic disorders [17,26,51,[80][81][82][83][84]. An inefficient GHR-JAK2-STAT5b signaling pathway results in fatty liver and adiposity in rodents and humans due to enhanced lipogenesis and reduced triglyceride secretion as well as reduced lipolysis [4,80,81].…”

Section: Other Functions Of Gh In the Regulation Of Body Weightmentioning

confidence: 99%

“…Thus, it has recently reported that in a sheep model, a point mutation in the SOCS2 gene not only resulted in higher body weight and size but also elevated leukocytes count in the milk as a sign of enhanced inflammatory response [90]. In addition, altered SOCS2 expression has also been associated with malignancies [84,[91][92][93]. Therefore, how to target SOCS2-regulated pathways without causing negative side effects that systemic and chronic reduction in SOCS2 protein might cause is still a challenge.…”

Section: Other Functions Of Gh In the Regulation Of Body Weightmentioning

confidence: 99%

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Fernández-Pérez¹,

Flores‐Morales²,

Guerra³

et al. 2016

Restricted Growth - Clinical, Genetic and Molecular Aspects

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Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic development, adulthood, and aging. GHR belongs to a family of receptors without intrinsic kinase activity. However, GH binding to homodimers of GHR results in a conformational change in the receptors and the associated tyrosine kinase Janus kinase 2 (JAK2) molecules. Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues, and subsequent JAK2-dependent and JAK2-independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal reorganization, and lipid and glucose metabolism. JAK2 phosphorylates STAT5b, which is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism, and gender dimorphism; although STAT1, 3, and 5a have also been shown to be recruited by the GHR. In addition, many transcripts are regulated independently of STAT5b as a result of GHR activation of Src, ERK, and PI3K-mTOR signaling pathways. The analysis of molecular mechanisms involved in inactivation of GHR-dependent signaling pathway is also imperative for understanding GH physiology. This is clearly illustrated in the case of hepatic GHR-JAK2-STAT5b activation where signal duration regulates gender differences in liver gene expression. An early step in the termination of GH-dependent signaling is removal of GHRs by endocytosis and ubiquitination. The level of ubiquitin ligase SOCS2 is constitutively low, but its expression is rapidly induced by GH. SOCS2 binding to GHR complex promotes their ubiquitination and subsequent proteasomal degradation, contributing to the termination of the GH intracellular signaling. Clinically relevant, SOCS2 is a key negative regulator of GH-dependent body growth and lipid and glucose homeostasis. Furthermore, several cytokines, growth factors, xenobiotics, and sex hormones can regulate SOCS2 protein level, which provides a mechanism for cross-talking where multiple factors can regulate GHR signaling during somatic development. A better understanding of this complex regulation in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth and metabolic disorders.

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SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

Abstract: Androgen induced SOCS2 ubiquitin ligase expression and inhibited GH signaling as well as cell proliferation and invasion in PCa, whereas reduced SOCS2 was present in castration-resistant cases. GH-signaling inhibitors might be a complementary therapeutic option for advanced PCa.

Cited by 44 publications

References 59 publications

SOCS proteins in regulation of receptor tyrosine kinase signaling

SOCS proteins in regulation of receptor tyrosine kinase signaling

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

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