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1.
Acta Pharmaceutica Sinica B ; (6): 1225-1239, 2022.
Article in English | WPRIM | ID: wpr-929366

ABSTRACT

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 β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-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.

2.
Acta Pharmaceutica Sinica B ; (6): 18-32, 2022.
Article in English | WPRIM | ID: wpr-929279

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

3.
Acta Pharmaceutica Sinica B ; (6): 309-321, 2021.
Article in English | WPRIM | ID: wpr-881138

ABSTRACT

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

4.
Acta Pharmaceutica Sinica B ; (6): 4008-4019, 2021.
Article in English | WPRIM | ID: wpr-922456

ABSTRACT

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation

5.
Acta Pharmaceutica Sinica B ; (6): 2738-2748, 2021.
Article in English | WPRIM | ID: wpr-888885

ABSTRACT

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

6.
Acta Pharmaceutica Sinica B ; (6): 723-733, 2020.
Article in English | WPRIM | ID: wpr-828847

ABSTRACT

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

7.
Acta Pharmaceutica Sinica B ; (6): 947-960, 2020.
Article in English | WPRIM | ID: wpr-828832

ABSTRACT

Hypoxia is a common feature of solid tumors. As transcription factors, hypoxia-inducible factors (HIFs) are the master regulators of the hypoxic microenvironment; their target genes function in tumorigenesis and tumor development. Intriguingly, both yes-associated protein (YAP) and its paralog transcriptional coactivator with a PDZ-binding motif (TAZ) play fundamental roles in the malignant progression of hypoxic tumors. As downstream effectors of the mammalian Hippo pathway, YAP and/or TAZ (YAP/TAZ) are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2 (LATS1/2)-MOB kinase activator 1 (MOB1) complex, which restricts the transcriptional activity of YAP/TAZ. However, dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes, most of which are closely related to cancer. Herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia, describe current agents and therapeutic strategies targeting the hypoxia-YAP/TAZ axis, and highlight questions that might have a potential impact in the future.

8.
Acta Pharmaceutica Sinica B ; (6): 1426-1439, 2020.
Article in English | WPRIM | ID: wpr-828798

ABSTRACT

The membrane protein claudin-3 (CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both and Of interest, CLDN3 undergoes -palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3 Moreover, the deprivation of -palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins. Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis Thus, our work reveals -palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 -palmitoylation might be a potential strategy for ovarian cancer therapy.

9.
Acta Pharmaceutica Sinica B ; (6): 484-495, 2019.
Article in English | WPRIM | ID: wpr-774961

ABSTRACT

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both and . Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.

10.
Acta Pharmaceutica Sinica ; (12): 29-32, 2016.
Article in Chinese | WPRIM | ID: wpr-505086

ABSTRACT

Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs.

11.
Article in Chinese | WPRIM | ID: wpr-503636

ABSTRACT

Aberrant activation of the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(PKB,Akt)-mammalian target of rapamycin(mTOR) pathway is commonly observed in human cancer and is critical for cell survival, proliferation and differentiation.A variety of small molecule inhibitors targeting PI3K-Akt-mTOR pathway are under clinical studies.This review will summarize the recent studies in terms of the PI3K-Akt-mTOR signaling pathway and cancer,research progress of the antitumor activity possessed by PI3K-Akt-mTOR inhibitors,as well as the recent research in the related field conducted by our group.

12.
Article in Chinese | WPRIM | ID: wpr-406397

ABSTRACT

Objective To investigate the chemical constituents of Citrus medica var. sareodactylis from Sichuan province, and to provide evidence for the development and utilization and quality evaluation of the medicinal material.Methods Various chromatographic techniques were used to purify the components of this herb. Compounds were identi-fied by their physical characteristics and spectral feature. Results Seven compounds were isolated from Citrus medica var. sarcodactylis, and they were identified as sibiricol (Ⅵ), 7-methylesculetin (Ⅶ), bergapten (Ⅷ), sigmasteryl acetate(Ⅸ), 5-methoxyfurfural(Ⅹ), limonin(Ⅺ), daucosterol (Ⅻ). Conclusion Compound Ⅵ, Ⅶ and Ⅸ are isolated from plants of Rutaceae for the first time.

13.
Article in Chinese | WPRIM | ID: wpr-579616

ABSTRACT

Objective To establish the determination of prim-O-glucosylcimifugin in Biyan Tablets by HPLC.Methods The HPLC determination was carried out on Diamonsil C18 column(4.6 mm? 250 mm,5 ? m).The mobile phase consisted of methanol-acetonirile-H2O(18 :12 :70) with a flow rate of 1.0 mL/min,and the ultraviolet detection wavelength was set at 254 nm.Results Prim-O-glucosylcimifugin showed a good linearity in the range of 0.1888~ 1.534 ? g with the peak area score,the coefficient was 0.9997,and the average recovery was 101.74 %(RSD=2.97 %).Conclusion The method is accurate and reliable,and can be used for the quality control of Biyan Tablets.

14.
Article in Chinese | WPRIM | ID: wpr-575573

ABSTRACT

Objective To study the galactagogue effect of Maidang Rutong Granules on the lactation rats.Methods The milk volume,morphology of mammary gland,serum prolactin level and pituitary acidophil number in lactation rats and the growth improvement in suckling mice were observed after administrating various dosages of Maidang Rutong Granules to lactation rats by gastric gavage.Results Maidang Rutong Granules can promote the dilation and hyperplasia of acinus cavity and conduit in mammary gland,reduce the mammary interlobular fat connective tissue,significantly increase pituitary acidophil number and serum prolactin level,increase the milk volume of lactation rats and their offspring's body weight.Conclusion Maidang Rutong Granules exhibit significant galactagogue effect on lactation rats.

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