spontaneous-murine-model-of-anaplastic-thyroid-cancer

Spontaneous Murine Model of Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy with a dismal prognosis. There is an urgent need for more in-depth research on the ...

Shenzhen Bay laboratory

The family with sequence similarity 20, member C (Fam20C), a Golgi casein kinase, has been recently regarded as a potential therapeutic target for the treatment of triple negative breast cancer (TNBC). Lacking enzyme activity center has been becoming an obstacle to the development of small-molecule inhibitors of Fam20C. Herein, we combined in silico high-throughput screening with chemical synthesis methods to obtain a new small-molecule Fam20C inhibitor 3r, which exhibited desired anti-proliferative activities against MDA-MB-231 cells and also inhibited migration. Subsequently, the enzymatic assay, molecular docking, and molecular dynamics (MD) simulations were carried out for validating that 3r could bind to Fam20C. In addition, 3r was found to induce apoptosis via the mitochondrial pathway in MDA-MB-231 cells as well as to inhibit cell migration. Moreover, we demonstrated that 3r inhibited tumor growth in vivo and thereby having a good therapeutic potential on TNBC. Taken together, these results suggest that 3r may be a novel Fam20C inhibitor with anti-proliferative and apoptosis-inducing activities, which would shed light on discovering more small-molecule drugs for the future TNBC therapy.

Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in  small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.

Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions.

Ketamine is widely used for cancer pain treatment in clinic, and has been shown to inhibit various tumor cells growth. However, the effect of ketamine on ovarian cancer cells growth and the downstream molecules has not been defined. In the present study, we found that ketamine significantly inhibited the proliferation and survival of six ovarian cancer cell lines. Moreover, ketamine induced ovarian cancer cell cycle arrest, apoptosis, and inhibited colony formation capacity. Since lncRNAs have been identified as key regulators of cancer development, we performed bioinformatics analysis of a GEO dataset and found fourteen significantly altered lncRNAs in ovarian cancer patients. We then investigated the effect of ketamine on these lncRNAs, and found that ketamine regulated the expression of lncRNA PVT1. Mechanistically, ketamine regulated P300-mediated H3K27 acetylation activation in the promoter of PVT1. Our RNA immunoprecipitation experiment indicated that PVT1 bound histone methyltransferase enhancer of zeste homolog 2 (EZH2), and regulated the expression of target gene, including p57, and consequently altered ovarian cancer cell biology. Our study revealed that ketamine could be a potential therapeutic strategy for ovarian cancer patients.

Ketamine Inhibits Ovarian Cancer Cell Growth by Regulating the lncRNA-PVT1/EZH2/p57 Axis.

Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies for nasopharyngeal carcinoma (NPC) patients. Unfortunately, resistance is a major obstacle in the clinical management of NPC patients. We prove that the expression level of high-mobility group box 1 (HMGB1) is dramatically increased in resistant NPC cells than that in sensitive cells. HMGB1 induces the expression and secretion of IL6, which leads to constitutive autocrine activation of the JAK2/STAT3 pathway and eventually contributes to chemoresistance in NPC cells. Long non-coding RNAs (lncRNAs) have been identified as key regulators involved in drug resistance. In this study, using GO analysis of the biological process and differential expression analysis, we find 12 significantly altered IncRNAs in NPC cell lines, which may be involved in regulating gene expression. Furthermore, we determine that elevated lncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of the lncRNA MIAT/HMGB1 axis, inhibition of JAK2/STAT3, or neutralization of IL6 by antibodies significantly re-sensitizes resistant NPC cells to cisplatin in resistant NPC cells. Moreover, we provide the  evidence that the deficiency of HMGB1 reduces cisplatin-resistant tumor growth. Most importantly, we provide clinical evidence showing that the expression level of the lncRNA MIAT/HMGB1/IL6 axis is elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by the lncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities for lncRNA MIAT, HMGB1, and IL6 as biomarkers for chemoresistance and targets for developing novel strategies to overcome resistance in NPC patients.

Article	Year
Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer. European journal of medicinal chemistry\| PubMed ID: 33316691	2021
Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions. Journal of medicinal chemistry\| PubMed ID: 33650861	2021
Ketamine Inhibits Ovarian Cancer Cell Growth by Regulating the lncRNA-PVT1/EZH2/p57 Axis. Frontiers in genetics\| PubMed ID: 33763107	2020
lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma. Frontiers in oncology\| PubMed ID: 34094941	2021

Leiming Wang

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