Dominant‐negative effect of truncated mannose 6‐phosphate/insulin‐like growth factor II receptor species in cancer

Kreiling, Jodi L.; Montgomery, Michelle A.; Wheeler, Joseph R.; Kopanic, Jennifer L.; Connelly, Christopher M.; Zavorka, Megan E.; Allison, Jenna L.; MacDonald, Richard G.

doi:10.1111/j.1742-4658.2012.08652.x

Cited by 16 publications

(9 citation statements)

References 55 publications

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“…Similarly, the overexpression of the metalloproteinases ADAM17 and ADAM28, which specifically act on IGFBP3, favors cancer cells proliferation by enhancing IGF1 bioavailability [ 50 , 51 ]. In addition, loss-of-heterozygosity of IGF2R favors the interaction between IGF2 and IGF1R in different tumor types [ 52 , 53 ]. Finally, alterations in intracellular signaling molecules can alter IGF equilibrium.…”

Section: The Igf System In Cancermentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

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The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.

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Section: The Igf System In Cancermentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

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“…IGF-2R plays a critical role in regulating the bioavailability of extracellular proteolytic enzyme and growth factors [26]. It clears IGF-2 from the cell surface to attenuate signaling, and has been shown to function as a tumor suppressor in a variety of cancer, including lung cancer [27][28][29]. Previous study in IGF-2-overexpressing rhabdomyosarcomas cells has shown that AKT phosphorylation on Ser473 may be the key target residue for PTEN to modulate the effects of IGF-2 on activating the PI3K/AKT pathways [28].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer

Mao

Xue

Smoake

et al. 2016

The Journal of Nutritional Biochemistry

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Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032-0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.

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“…Transient expression of soluble receptors was done in HEK 293 cells as described previously [ 83 ]. Transfection was carried out by a modification of the calcium phosphate method [ 84 ].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of insulin-like growth factor II (IGF-II)-dependent cell growth by multidentate pentamannosyl 6-phosphate-based ligands targeting the mannose 6-phosphate/IGF-II receptor

et al. 2016

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The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds M6P-capped ligands and IGF-II at different binding sites within the ectodomain and mediates ligand internalization and trafficking to the lysosome. Multivalent M6P-based ligands can cross-bridge the M6P/IGF2R, which increases the rate of receptor internalization, permitting IGF-II binding as a passenger ligand and subsequent trafficking to the lysosome, where the IGF-II is degraded. This unique feature of the receptor may be exploited to design novel therapeutic agents against IGF-II-dependent cancers that will lead to decreased bioavailable IGF-II within the tumor microenvironment. We have designed a panel of M6P-based ligands that bind to the M6P/IGF2R with high affinity in a bivalent manner and cause decreased cell viability. We present evidence that our ligands bind through the M6P-binding sites of the receptor and facilitate internalization and degradation of IGF-II from conditioned medium to mediate this cellular response. To our knowledge, this is the first panel of synthetic bivalent ligands for the M6P/IGF2R that can take advantage of the ligand-receptor interactions of the M6P/IGF2R to provide proof-of-principle evidence for the feasibility of novel chemotherapeutic agents that decrease IGF-II-dependent growth of cancer cells.

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Dominant‐negative effect of truncated mannose 6‐phosphate/insulin‐like growth factor II receptor species in cancer

Cited by 16 publications

References 55 publications

Novel Regulators of the IGF System in Cancer

Novel Regulators of the IGF System in Cancer

MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer

Inhibition of insulin-like growth factor II (IGF-II)-dependent cell growth by multidentate pentamannosyl 6-phosphate-based ligands targeting the mannose 6-phosphate/IGF-II receptor

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