RIPK2: a promising target for cancer treatment.

As an essential mediator of inflammation and innate immunity, the receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is responsible for transducing signaling downstream of the intracellular peptidoglycan sensors nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2), which will further activate nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, leading to the transcription activation of pro-inflammatory cytokines and productive inflammatory response. Thus, the NOD2-RIPK2 signaling pathway has attracted extensive attention due to its significant role in numerous autoimmune diseases, making pharmacologic RIPK2 inhibition a promising strategy, but little is known about its role outside the immune system. Recently, RIPK2 has been related to tumorigenesis and malignant progression for which there is an urgent need for targeted therapies. Herein, we would like to evaluate the feasibility of RIPK2 being the anti-tumor drug target and summarize the research progress of RIPK2 inhibitors. More importantly, following the above contents, we will analyze the possibility of applying small molecule RIPK2 inhibitors to anti-tumor therapy.

WSB1 regulates c-Myc expression through ß-catenin signaling and forms a feedforward circuit.

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the ß-catenin pathway. Mechanistically, WSB1 affected ß-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor ß-TRCP recruitment, which inhibited the ubiquitination of ß-catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy.

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality. In this review, we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

One therapeutic approach for triple-negative breast cancer: Checkpoint kinase 1 inhibitor AZD7762 combination with neoadjuvant carboplatin.

Carboplatin treatment is associated with potential benefits in practice in the neoadjuvant chemotherapy for Triple-negative breast cancer (TNBC) patients. In order to enhance its anti-tumor effects, new concepts for successful combination therapy are needed. Here, we interestingly found that the combination treatment of carboplatin with the Chk1 inhibitor AZD7762 synergistically inhibits TNBC cell growth in multiple TNBC cell lines in vitro. Mechanistically, we proved that prolonged carboplatin-treated induce cell mitotic arrest, and cells would fail to initiate the G2-M transition following the inhibition of the Chk1 pathway, leading to accumulation of DNA lesions. With this drug-in-combination treatment, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is remarkably enhanced, which subsequently drives tumor cells multinucleation, polyploidization and apoptosis. Thus, our findings not only propose Chk1 as a therapeutic target for combination therapy with DNA-damaging agents such as carboplatin in TNBC, but also highlight that the induction of mitotic catastrophe could be considered as an alternative strategy for TNBC therapy.

Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis.

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.

LncRNA-MM2P Identified as a Modulator of Macrophage M2 Polarization.

M2 polarization of macrophages is essential for their function in immunologic tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophage-mediated promotion of tumorigenesis, tumor growth in vivo, and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis.

Cellular Senescence and Anti-Cancer Therapy.

BACKGROUND: Cellular senescence is generally understood as a permanent cell cycle arrest stemming from different causes. The mechanism of cellular senescence-induced cell cycle arrest is complex, involving interactions between telomere shortening, inflammations and cellular stresses. In recent years, a growing number of studies have revealed that cellular senescence could mediate the cancer progression of neighboring cells, but this idea is controversial and contradictory evidence argues that cellular senescence also contributes to tumor suppression. OBJECTIVE: Given that the complicated role of senescence in various physiological and pathological scenarios, we try to clarify the precise contribution role of cellular senescence to tumor progression. METHODS: Search for the information in a large array of relevant articles to support our opinion. RESULTS: We discuss the relatively widespread occurrence of cellular senescence in cancer treatment and identify the positive and negative side of senescence contributed to tumor progression. CONCLUSION: We argue that the availability of pro-senescence therapy could represent as a promising regimen for managing cancer disease, particularly with regard to the poor clinical outcome obtained with other anticancer therapies.