In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma

Pozzi, Samantha; Fulciniti, Mariateresa; Hua, Yan; Vallet, Sonia; Eda, Homare; Patel, Kishan; Santo, Loredana; Cirstea, Diana; Hideshima, Teru; Schirtzinge, Linda; Kuhstoss, Stuart; Anderson, Kenneth C.; Munshi, Nikhil C.; Scadden, David T.; Kronenberg, Henry M.

doi:10.1016/j.bone.2013.01.012

Cited by 67 publications

(42 citation statements)

References 34 publications

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“…Furthermore, an antibody targeting the extracellular domain of CKAP4 suppressed tumorigenesis in DKK-1-expressing cell lines and in a mouse xenograft model. These findings are consistent with published data showing that anti-DKK-1 antibodies impair growth of engrafted human cancers, such as multiple myeloma, in mice (10,20,21). However, given that DKK-1 may also suppress tumors by inhibiting Wnt signaling, an antibody to CKAP4 may have more specific, antiproliferative effects that spare the potential tumor suppressor function of DKK-1.…”

Section: Discussionsupporting

confidence: 92%

CKAP4 is identified as a receptor for Dickkopf in cancer cells

Bhavanasi¹,

Speer²,

Klein³

2016

Journal of Clinical Investigation

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C o m m e n t a r y2 Divergent functions for Dickkopf-1Dickkopf-1 (DKK-1) was first identified in Xenopus as an extracellular antagonist of canonical Wnt signaling (1), a fundamental pathway that controls cell fate, survival, and proliferation. Aberrant activation of Wnt signaling also drives tumorigenesis in colon, breast, hepatocellular, and many other cancers (2-4). As a Wnt signaling inhibitor, DKK-1 suppresses tumorigenesis in some cancer cells, including renal cell carcinoma (5), breast carcinoma (6), and colon cancer cells (7-9). However, DKK-1 is often elevated in cancers, is associated with aggressive disease, and promotes proliferation in multiple cell types (10, 11), suggesting that DKK-1 also functions independently of Wnt inhibition. In this issue, Kimura and colleagues investigate the molecular events that lead to DKK-1-induced cancer cell proliferation (12). Their work has identified a Wnt-independent signaling role for DKK-1 through interaction with the type-II transmembrane protein cytoskeleton-associated protein 4 (CKAP4; also known as p63, ERGIC-63, or CLIMP-63). These findings also indicate that the DKK-1/CKAP4 interaction represents a promising therapeutic target for cancer.CKAP4 is a DKK-1 receptor that activates AKT signaling DKK family proteins contain two cysteinerich domains (CRDs). The C-terminal CRD (CRD-2) of DKK-1 inhibits Wnt signaling by directly binding to the Wnt coreceptors LRP5/6 (LDL-related proteins 5 and 6), thereby preventing interaction with Wnts, and by binding to the transmembrane protein KREMEN to promote LRP5/6 internalization (11, 13-15). Kimura et al. have now demonstrated that CRD-1 of DKK-1 binds to CKAP4 at the apical surface of epithelial cells (Figure 1 and ref. 12). Furthermore, DKK-1 binds to CKAP4 with high affinity that is comparable to but independent of its interaction with LRP5/6. Upon DKK-1 binding, CKAP4 recruits phosphatidylinositol-3 kinase (PI3K) to its cytoplasmic domain through interaction with the SH3 domain of the p85α subunit of PI3K. Through this mechanism, DKK-1 activates AKT and promotes proliferation. These findings substantially expand our understanding of DKK-1 signaling mechanisms and define a previously unrecognized input to the PI3K/AKT pathway.The findings of Kimura et al. also raise questions about the potential functions of other DKK family members (12). The DKK family comprises four conserved proteins, DKK-1 through -4 (and DKK-like 1, which lacks the CRDs). DKK-1 antagonizes Wnt/β-catenin signaling, activates AKT (as shown here), and may also activate JNK signaling (16); however, the functions of other DKK family members are less well characterized. DKK-2 and -4 antagonize Wnt signaling, similar to DKK-1, but DKK-2 can also activate canonical Wnt signaling depending on the cellular context (11,17). In contrast, DKK-3 positively regulates Wnt signaling (18) and binds to integrin α6b to induce myogenesis in zebrafish (19). As Kimura and colleagues point out (12), CRD-1 is highly conserved among the four Dkk genes, raising the possib...

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Section: Discussionsupporting

confidence: 92%

CKAP4 is identified as a receptor for Dickkopf in cancer cells

Bhavanasi¹,

Speer²,

Klein³

2016

Journal of Clinical Investigation

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“…It is noteworthy that multiple studies provided proof of concept that Dkk1 targeting by immunotherapy can be used efficiently in both protective and therapeutic manners against cancer. [42][43][44][45][46][47] Sato et al 46 found that anti-Dkk1 treatment was able to induce apoptosis of A549 lung cancer cells (which express high levels of Dkk1) by an unknown mechanism, which we believe could be the one we describe here. Furthermore, tumors formed in nude mice following A549 cells injection were significantly smaller in animals treated with anti-Dkk1 compared with controls, demonstrating that Dkk1 targeting by antibodies can efficiently inhibit tumor growth in vivo.…”

Section: Discussionmentioning

confidence: 54%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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In multicellular organisms, a tight control of cell death is required to ensure normal development and tissue homeostasis. Improper function of apoptotic or survival pathways can not only affect developmental programs but also favor cancer progression. Here we describe a novel apoptotic signaling pathway involving the transmembrane receptor Kremen1 and its ligand, the Wnt-antagonist Dickkopf1. Using a whole embryo culture system, we first show that Dickkopf1 treatment promotes cell survival in a mouse model exhibiting increased apoptosis in the developing neural plate. Remarkably, this effect was not recapitulated by chemical Wnt inhibition. We then show that Dickkopf1 receptor Kremen1 is a bona fide dependence receptor, triggering cell death unless bound to its ligand. We performed Wnt-activity assays to demonstrate that the pro-apoptotic and anti-Wnt functions mediated by Kremen1 are strictly independent. Furthermore, we combined phylogenetic and mutagenesis approaches to identify a specific motif in the cytoplasmic tail of Kremen1, which is (i) specifically conserved in the lineage of placental mammals and (ii) strictly required for apoptosis induction. Finally, we show that somatic mutations of kremen1 found in human cancers can affect its pro-apoptotic activity, supporting a tumor suppressor function. Our findings thus reveal a new Wnt-independent function for Kremen1 and Dickkopf1 in the regulation of cell survival with potential implications in cancer therapies.

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“…Numerous studies have shown that DKK1 was implicated in the control of various pathological and physiological processes, including adult hippocampal neurogenesis [5], osteoclastogenesis [6], tumor cell proliferation, survival, migration and invasion [7,8]. However, the role of DKK1 in tumor biology is controversial.…”

Section: Introductionmentioning

confidence: 99%

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

et al. 2013

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BackgroundRecently several reports have indicated that elevated expression of DKK1 is tightly associated with the progression of hepatocellular carcinoma (HCC). However, the biological function of DKK1 in HCC has not yet been well documented.MethodsIn this study, the role of DKK1 in tumor cell proliferation, migration and invasion was investigated using MTT, colony formation, wound scratch, transwell assays, and also human HCC samples.ResultsBoth gain- and loss-of-function studies showed that DKK1 did not influence the tumor cell proliferation and colony formation, while dramatically promoted HCC cell migration and invasion. Subsequent investigations revealed that β-catenin was an important target of DKK1. The blocking of β-catenin by pharmacological inhibitor antagonized the function of DKK1, whereas introduction of β-catenin by transfection with plasmids or treatment with GSK3β inhibitor phenocopied the pro-migration and pro-invasion effects of DKK1. We further disclosed that DKK1 exerted its pro-invasion function, at least in part, by promoting β-catenin expression, in turn, upregulating the expression of matrix metalloproteinase 7 (MMP7), which was independent of the canonical Wnt signaling pathway. Moreover, introduction of MMP7 significantly enhanced the ability of HCC cells to invade extracellular matrix gel in vitro. Consistently, in human HCC tissues, DKK1 level was positively correlated with β-catenin expression, as well as tumor metastasis.ConclusionTaken together, these results demonstrated that DKK1 is overexpressed in HCC; moreover, ectopic expression DKK1 promotes HCC cell migration and invasion at least partly through β-catenin/MMP7 signaling axis, suggesting that DKK1 may be a promising target for HCC therapy.

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In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma

Cited by 67 publications

References 34 publications

CKAP4 is identified as a receptor for Dickkopf in cancer cells

CKAP4 is identified as a receptor for Dickkopf in cancer cells

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

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