Raloxifene, identified as a novel LSD1 inhibitor, suppresses the migration of renal cell carcinoma

Aim: As an important epigenetic modulator, histone lysine-specific demethylase 1 (LSD1) has been proved to be associated with the progression of renal cell carcinoma (RCC). Discovering novel LSD1 inhibitors offers therapeutic potential for RCC treatment. Methods & Results: We identified raloxifene as a novel LSD1 inhibitor (IC50 = 2.08 μM) through small compound library screening. Molecular docking indicated raloxifene might bind LSD1 in the flavin adenine dinucleotide (FAD) binding cavity in a reversible manner. Cell viability and migration assays showed raloxifene could suppress the proliferation and migration of RCC cells bearing overexpressed LSD1. Conclusion: Our findings indicated that LSD1 might be a promising therapeutic target for RCC and that raloxifene could serve as a lead compound for further anti-RCC metastasis drug discovery.

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TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma

10.31234/osf.io/cm9wj ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Renal Cell Carcinoma ◽

Cell Proliferation ◽

Cell Carcinoma ◽

Renal Cell ◽

Lymphatic Invasion ◽

Cancer Specific Survival ◽

Candidate Target ◽

Candidate Target Gene ◽

And Migration

TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression andits function in renal cell carcinoma (RCC) are still unknown. Here in this study, weinvestigated the clinical significance of TRIM44 and its biological function in RCC.TRIM44 overexpression was significantly associated with clinical M stage, histologictype (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028,respectively). Moreover, TRIM44 overexpression was significantly associated withpoor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function andloss-of-function studies using TRIM44 and siTRIM44 transfection showed thatTRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1and 769P. To further investigate the role of TRIM44 in RCC, we performed integratedmicroarray analysis in Caki1 and 769P cells and explored the data in the Oncominedatabase. Interestingly, FRK was identified as a promising candidate target gene ofTRIM44, which was downregulated in RCC compared with normal renal tissues. Wefound that cell proliferation was inhibited by TRIM44 knockdown and then recoveredby siFRK treatment. Taken together, the present study revealed the associationbetween high expression of TRIM44 and poor prognosis in

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Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01832-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Aurore Dumond ◽

Etienne Brachet ◽

Jérôme Durivault ◽

Valérie Vial ◽

Anna K. Puszko ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Cell Metabolism ◽

Boyden Chamber ◽

Migration Ability ◽

Cell Renal Cell Carcinoma ◽

Immunodeficient Mice ◽

And Migration

Abstract Background Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway. Methods We correlated the NRP1, 2 levels to patients’ survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs. Results Knock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients. Conclusions Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.

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Downregulation of miR-193a-3p inhibits cell growth and migration in renal cell carcinoma by targeting PTEN

Tumor Biology ◽

10.1177/1010428317711951 ◽

2017 ◽

Vol 39 (6) ◽

pp. 101042831771195 ◽

Cited By ~ 9

Author(s):

Lingqi Liu ◽

Yanqin Li ◽

Shuchao Liu ◽

Qixin Duan ◽

Liang Chen ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Growth ◽

Cell Carcinoma ◽

Renal Cell ◽

Cell Growth And Migration ◽

And Migration

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Exploiting Synthetic Lethal Network for Precision Treatment of Clear Cell Renal Cell Carcinoma

10.21203/rs.3.rs-958499/v1 ◽

2021 ◽

Author(s):

Zhicheng Liu ◽

Dongxu Lin ◽

Linmeng Zhang ◽

Chen Yang ◽

Bin Guo ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Large Scale ◽

Target Genes ◽

Clear Cell ◽

Therapeutic Potential ◽

Synthetic Lethality ◽

Treatment Modalities ◽

Cell Renal Cell Carcinoma

Abstract Background The emerging of targeted therapies has revolutionized the treatment modalities of advanced clear cell renal cell carcinoma (ccRCC) over the past fifteen years. However, lack of personalized treatment limits the development of effective clinical guidelines and improvement of patient prognosis. In this study, large-scale genomic profiles of ccRCC cohorts were exploited for conducting an integrative analysis. Method Based on synthetic lethality (SL), a concept that simultaneous losses of two genes cause cell death while a single loss does not, we sought to develop a computational pipeline to infer potential SL partners of ccRCC. Drug response prediction were received from three pharmacological databases to select agents which are likely to be effective in precisely treating patients with target gene mutation. Results We developed a credible method to identify SL pairs and determined a list of 72 candidate pairs which might be utilized to selectively eliminate tumors with genetic aberrations through SL partners of specific mutations. Further analysis identified BRD4 and PRKDC as novel medicine targets for patients with BAP1 mutations. After mapping these target genes to comprehensive drug datasets, two agents (BI-2536 and PI-103) were found to have considerable therapeutic potential in BAP1 mutant tumors. Conclusion Overall, our findings provide insight into the overview of ccRCC mutation patterns and offer novel opportunities for improving individualized cancer treatment.

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