scholarly journals Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels

2021 ◽  
Author(s):  
Isabel Kurth ◽  
Norihiro Yamaguchi ◽  
Celia Andreu-Agullo ◽  
Helen S. Tian ◽  
Subhasree Sridhar ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Phase 1 ◽  
Creatine Transporter ◽  
Tumor Cell Apoptosis ◽  
Creatine Kinase B ◽  
Colon Cancer Progression ◽  
Creatine Metabolism

ABSTRACTColorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 creatine transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels and induces tumor cell apoptosis in CRC. RGX-202 suppressed tumor growth across KRAS wild-type and KRAS mutant xenograft, syngeneic and patient-derived xenograft colorectal cancers. Anti-tumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5- fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in metastatic CRC patients enrolled in a Phase-1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of pre-clinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, revealing a critical target for CRC.

NEAT1 promotes colon cancer progression through sponging miR‐495‐3p and activating CDK6 in vitro and in vivo

2019 ◽  
Vol 234 (11) ◽  
pp. 19582-19591 ◽  
Author(s):  
Zhiyun He ◽  
Jie Dang ◽  
Ailin Song ◽  
Xiang Cui ◽  
Zhijun Ma ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression

scholarly journals SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Ali R. Nasiri ◽  
Marcos R. Rodrigues ◽  
Zongyu Li ◽  
Brooks P. Leitner ◽  
Rachel J. Perry
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Colon Adenocarcinoma ◽  
Sglt2 Inhibitors ◽  
Multiple Tumor ◽  
Increased Risk ◽  
Colon Cancer Progression

Abstract Background Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking. Methods E0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni’s multiple comparisons test. Results Dapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth. Conclusions Taken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

scholarly journals Lnc HAGLR Promotes Colon Cancer Progression Through Sponging miR‐185‐5p and Activating CDK4 and CDK6 in vitro and in vivo

2020 ◽  
Vol Volume 13 ◽  
pp. 5913-5925 ◽  
Author(s):  
Weixuan Sun ◽  
Wenting Nie ◽  
Zhaoyi Wang ◽  
Haolong Zhang ◽  
Yezhou Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression

scholarly journals Knockdown of Lymphoid Enhancer factor 1 Inhibits Colon Cancer Progression In Vitro and In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e76596 ◽  
Author(s):  
Wen-Juan Wang ◽  
Yu Yao ◽  
Li-Li Jiang ◽  
Ting-Hua Hu ◽  
Jie-Qun Ma ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression ◽  
Enhancer Factor

scholarly journals Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 867 ◽  
Author(s):  
Goh ◽  
Tan ◽  
Goh ◽  
Chan ◽  
Pusparajah ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Citrus Fruit ◽  
Future Research ◽  
Fruit Peel ◽  
Chemopreventive Agents ◽  
Citrus Peel ◽  
Anti Cancer

The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive agents against cancer. One of the promising compounds under extensive research is nobiletin (NOB), a polymethoxyflavone (PMF) extracted exclusively from citrus peel. Not only does nobiletin itself exhibit anti-cancer properties, but its derivatives are also promising chemopreventive agents; examples of derivatives with anti-cancer activity include 3′-demethylnobiletin (3′-DMN), 4′-demethylnobiletin (4′-DMN), 3′,4′-didemethylnobiletin (3′,4′-DMN) and 5-demethylnobiletin (5-DMN). In vitro studies have demonstrated differential efficacies and mechanisms of NOB and its derivatives in inhibiting and killing of colon cancer cells. The chemopreventive potential of NOB has also been well demonstrated in several in vivo colon carcinogenesis animal models. NOB and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer (CRC) pathophysiology, including arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumour formation, reducing inflammatory effects and limiting angiogenesis. However, these substances have low oral bioavailability that limits their clinical utility, hence there have been numerous efforts exploring better drug delivery strategies for NOB and these are part of this review. We also reviewed data related to patents involving NOB to illustrate the extensiveness of each research area and its direction of commercialisation. Furthermore, this review also provides suggested directions for future research to advance NOB as the next promising candidate in CRC chemoprevention.

scholarly journals Secernin-1 Contributes to Colon Cancer Progression through Enhancing Matrix Metalloproteinase-2/9 Exocytosis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Shengtao Lin ◽  
Tao Jiang ◽  
Yang Yu ◽  
Huamei Tang ◽  
Su Lu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Matrix Metalloproteinase ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Bioinformatics Analysis ◽  
Tumor Development ◽  
Matrix Metalloproteinase 2 ◽  
Cancer Cell Proliferation ◽  
Colon Cancer Progression

Emerging evidence shows that exocytosis plays a key role in tumor development and metastasis. Secernin-1 (SCRN1) is a novel regulator of exocytosis. Our previous work identified SCRN1 as a tumor-associated gene by bioinformatics analysis of transcriptomes. In this study, we demonstrated the aberrant overexpression of SCRN1 at mRNA and protein level in colon cancer. We also revealed that overexpression of SCRN1 was significantly associated with the tumor development and poor prognosis. Experimentsin vitrovalidated that SCRN1 may promote cancer cell proliferation and secretion of matrix metalloproteinase-2/9 (MMP-2/9) proteins to accelerate tumor progression.

scholarly journals Overexpression of the transcribed ultraconserved region Uc.138 accelerates colon cancer progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuki Kuwano ◽  
Kensei Nishida ◽  
Kazuhito Rokutan
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Adenocarcinoma ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Nuclear Retention ◽  
Exon 2 ◽  
Potential Biomarker ◽  
Colon Cancer Progression

AbstractUltraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2β gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2β protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer.

scholarly journals The cables gene on chromosome 18Q regulates colon cancer progression in vivo

2005 ◽  
Vol 4 (8) ◽  
pp. 861-863 ◽  
Author(s):  
Sandra D. Kirley ◽  
Massimo D'Apuzzo ◽  
Gregory Y. Lauwers ◽  
Fiona Graeme-Cook ◽  
Daniel C. Chung ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression ◽  
Chromosome 18Q

scholarly journals Effects of a Chlorogenic Acid-Containing Herbal Medicine (LASNB) on Colon Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yanchu Li ◽  
Rong Pu ◽  
Lu Zhou ◽  
Dan Wang ◽  
Xianyong Li
Keyword(s):  
Colon Cancer ◽  
Herbal Medicine ◽  
Chlorogenic Acid ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Hematological Toxicity ◽  
Severe Toxicity

Background. Plant polyphenols, which contain phenolic acids such as chlorogenic acid (CGA), can be used for the treatment of gastrointestinal cancer and have gained increasing attention in recent years. In this study, we explored a novel CGA-containing herbal medicine named LASNB, which was extracted from Lonicera japonica Thunb., Agrimonia eupatoria L., and Scutellaria barbata D.Don. Methods. CGA in LASNB was analyzed using high-performance liquid chromatography (HPLC). The biological functions and molecular mechanisms of LASNB were investigated in colon cancer cell lines (HCT116, HCT15, and CT26), a normal colon cell line (NCM460), and a CT26 xenograft model. To assess safety, hematological toxicity and pathology of the liver, kidney, and lung were evaluated. Results. LASNB suppressed HCT116, HCT15, and CT26 colon cancer progression by inhibiting proliferation capacity, promoting cell apoptosis, and suppressing cell migration both in vitro and in vivo. Investigation into the underlying molecular mechanism indicated that LASNB suppressed the activation of receptor tyrosine kinase- (RTK-) MEK-ERK and NF-κB pathways. With regard to safety, slight interstitial vascular congestion in the lung was observed, but no severe pathological or hematological toxicity was detected. Conclusions. We found that LASNB suppressed the progression of colon cancer via the RTK-MEK-ERK and NF-κB pathways, with no severe toxicity observed. Therefore, LASNB has the potential to be used as a supplementary herbal medicine for the treatment of colon cancer.

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