β-Catenin Small Interfering RNA Successfully Suppressed Progression of Multiple Myeloma in a Mouse Model

Ashihara, Eishi; Kawata, Eri; Nakagawa, Yoko; Shimazaski, Chihiro; Kuroda, Junya; Taniguchi, Kyoko; Uchiyama, Hitoji; Tanaka, Ray; Yokota, Asumi; Takeuchi, Miki; Kamitsuji, Yuri; Inaba, Tohru; Taniwaki, Masafumi; Kimura, Shinya; Maekawa, Taira

doi:10.1158/1078-0432.ccr-08-1350

Cited by 59 publications

(57 citation statements)

References 34 publications

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“…The downstream targets of the canonical ILP signaling include the survival pathway PI3K/Akt that can activate downstream targets like mTOR and FoxO/BAD/Bcl-2 but also inhibit GSK3b, resulting in the activation of the oncogenic b-catenin signaling pathway (Fleming et al 2008, Ashihara et al 2009). In the last decade, PI3K, Akt, mTOR, FoxO, BAD, Bcl-2, b-catenin, and other signaling molecules involved in cell survival and proliferation have been the subjects of investigation of many studies aiming at unraveling carcinogenic mechanisms.…”

Section: Insulin Resistance Infection and Cancermentioning

confidence: 99%

“…Such functions are evolutionarily conserved (Duckworth et al 1989, Klusza & Deng 2011, and accordingly, the stimulation of IGF1 axis may represent a common medium for both cancer and diabetes pathogenic processes, together with systemic inflammation and the associated increase in cytokine production (Nunez et al 2006, Dool et al 2011, Faria & Almeida 2012, Ferguson et al 2012, Fernandez-Real & Pickup 2012, Gallagher et al 2012. Except for the IGF2 receptor (IGF2R), following ligand binding, the kinase activity of ILP receptors is activated, leading to the phosphorylation of IR substrates in the cell membrane, which in turn i) activates phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), PI3K/Akt/forkhead box O (FoxO), and Ras/MAPK/extracellular signal-related kinase 1/2 (ERK-1/2) pathways, whose important roles in cancer cell growth and carcinogenesis have been reported (Alvino et al 2011, Tzivion et al 2011; and ii) inactivates glycogen synthase kinase 3b (GSK3b), the inhibitor of the oncogenic b-catenin signaling, through PI3K/Akt signaling pathway, resulting in b-catenin signaling activation that has been associated with cancer stemness and chemoresistance (Fleming et al 2008, Ashihara et al 2009; see Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Insulin resistance and cancer: the role of insulin and IGFs

Djiogue¹,

Kamdje²,

Vecchio³

et al. 2012

Endocrine-Related Cancer

229

188

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Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

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Section: Insulin Resistance Infection and Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin resistance and cancer: the role of insulin and IGFs

Djiogue¹,

Kamdje²,

Vecchio³

et al. 2012

Endocrine-Related Cancer

229

188

View full text Add to dashboard Cite

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“…In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5)(6)(7)(8)(9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10).…”

mentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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“…156 The canonical Wnt signaling pathway has an emerging role in multiple myeloma, in which the constitutively active β-catenin is relevant to tumor cell growth, survival, and migration. 157,158 To exploit this tumor dependence on Wnt signaling, small molecule compounds and interfering RNA targeting β-catenin have shown promise as therapeutic approaches in the treatment of the disease. 157,158 As already noted, GRP94 deficiency in human multiple myeloma cells resulted in apoptosis through inhibition of the Wnt-survivin pathway.…”

Section: Multiple Myelomamentioning

confidence: 99%

“…157,158 To exploit this tumor dependence on Wnt signaling, small molecule compounds and interfering RNA targeting β-catenin have shown promise as therapeutic approaches in the treatment of the disease. 157,158 As already noted, GRP94 deficiency in human multiple myeloma cells resulted in apoptosis through inhibition of the Wnt-survivin pathway. 70 Although the pan-Hsp90 inhibitors showed potential as therapeutic agents for multiple myeloma, the role of individual Hsp90 isoforms and family members in these treatments was not determined.…”

Section: Multiple Myelomamentioning

confidence: 99%

Hsp90 as a therapeutic target in endocrinology: current evidence

Ratajczak¹,

Ward²,

Walsh³

et al. 2015

RRED

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Abstract:The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and β in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system.

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β-Catenin Small Interfering RNA Successfully Suppressed Progression of Multiple Myeloma in a Mouse Model

Cited by 59 publications

References 34 publications

Insulin resistance and cancer: the role of insulin and IGFs

Insulin resistance and cancer: the role of insulin and IGFs

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Hsp90 as a therapeutic target in endocrinology: current evidence

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