Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells

Wallis, Nadav; Oberman, Froma; Shurrush, Khriesto A.; Germain, Nicolas; Greenwald, G.; Gershon, Tehila; Pearl, Talia; Abis, Giancarlo; Singh, Vikash; Singh, Amandeep; Sharma, Arun; Barr, Haim; Ramos, Andrés; Spiegelman, Vladimir S.; Yisraeli, Joel K.

doi:10.1080/15476286.2021.2010983

Cited by 50 publications

(26 citation statements)

References 69 publications

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“…Knockout of IGF2BPs also inhibited colony formation, migration, and in vivo tumor formation in renal cell carcinoma 786-0 and Caki-1 cells 62 . In addition, a small molecule inhibitor of IGF2BP1 suppressed cell migration and colony formation in soft agar in non-small-cell lung carcinoma H1299 cells 63 . We also found that knockdown of IGF2BPs with siRNA decreased cell proliferation in breast cancer MDA-MB-231 cells and gastric cancer MKN1 cells (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 97%

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types

Hwa

Jang

et al. 2022

Exp Mol Med

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N6-Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial–mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.

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Section: Discussionmentioning

confidence: 97%

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types

Hwa

Jang

et al. 2022

Exp Mol Med

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“…A synergistic phenomenon between oncogenic KRAS mutation and IGF2BP1 overexpression has been documented by Rosenfeld et al in murine and human lung cancer models [ 112 ]. KRASG12V mutant/IGF2BP1 transgenic mice showed an increased tumor development linked to KRAS mRNA attachment to IGF2BP1 [ 113 ]. Non-small-cell lung cancer cells with annexin A2 (ANXA2) knockdown had an increase in p53 and cell cycle arrest [ 114 ].…”

Section: Rna Binding Protein/translocation Of Rna To Exosomesmentioning

confidence: 99%

Extracellular Vesicle (EVs) Associated Non-Coding RNAs in Lung Cancer and Therapeutics

Paramanantham

Asfiya

Das

et al. 2022

IJMS

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Lung cancer is one of the most lethal forms of cancer, with a very high mortality rate. The precise pathophysiology of lung cancer is not well understood, and pertinent information regarding the initiation and progression of lung cancer is currently a crucial area of scientific investigation. Enhanced knowledge about the disease will lead to the development of potent therapeutic interventions. Extracellular vesicles (EVs) are membrane-bound heterogeneous populations of cellular entities that are abundantly produced by all cells in the human body, including the tumor cells. A defined class of EVs called small Extracellular Vesicles (sEVs or exosomes) carries key biomolecules such as RNA, DNA, Proteins and Lipids. Exosomes, therefore, mediate physiological activities and intracellular communication between various cells, including constituent cells of the tumor microenvironment, namely stromal cells, immunological cells, and tumor cells. In recent years, a surge in studying tumor-associated non-coding RNAs (ncRNAs) has been observed. Subsequently, studies have also reported that exosomes abundantly carry different species of ncRNAs and these exosomal ncRNAs are functionally involved in cancer initiation and progression. Here, we discuss the function of exosomal ncRNAs, such as miRNAs and long non-coding RNAs, in the pathophysiology of lung tumors. Further, the future application of exosomal-ncRNAs in clinics as biomarkers and therapeutic targets in lung cancer is also discussed due to the multifaceted influence of exosomes on cellular physiology.

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“…Oncofetal RNA-binding protein (Igf2bp1) is responsible for different types of cancer [ 138 ] and can synergize mutation to KRAS. Researchers synthesized the small-molecule inhibitor 7773 ( Table 4 ), which can bind with the hydrophobic surface of Igf2bp1 in the KH3 and KH4 domain and inhibit the binding of KRAS 6 RNA in vitro.…”

Section: Small-molecule Ras Inhibitorsmentioning

confidence: 99%

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies

Shetu

Bandyopadhyay

2022

IJMS

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Mutations of RAS oncogenes are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation to generate solid tumors in many types of cancer such as pancreatic carcinoma (over 80%), colon carcinoma (40–50%), lung carcinoma (30–50%), and other types of cancer. Once described as ‘undruggable’, RAS proteins have become ‘druggable’, at least to a certain extent, due to the continuous efforts made during the past four decades. In this account, we discuss the chemistry and biology (wherever available) of the small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins that were published in the past decades. Commercial drugs, as well as investigational molecules from preliminary stages to clinical trials, are categorized and discussed in this study. In summary, this study presents an in-depth discussion of RAS proteins, classifies the RAS superfamily, and describes the molecular mechanism of small-molecule RAS inhibitors

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Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells

Cited by 50 publications

References 69 publications

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types

Extracellular Vesicle (EVs) Associated Non-Coding RNAs in Lung Cancer and Therapeutics

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies

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