Xuejun Wang

University of South Dakota, Basic Biomedical Sciences, Faculty Member

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An established scientist has centered his research on protein quality control and degradation in (patho)physiology.
Phone: +01 605 658-6345
Address: 414 E Cark Street
Vermillion, SD 57069
USA

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Melissa Gray

University of Wisconsin-Madison

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Maria-Corina Serban

University Of Medicine And Pharmacy Timisoara

Ioana Mozos

University Of Medicine And Pharmacy Timisoara

Michael J. Gonzalez

Universidad de Puerto Rico Rio

Moez Alislam Faris

University of Sharjah

Xanthippi Alexi

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Dr. Anika Niambi Al-Shura, BSc, MSOM, PhD

Independent Academic Research Studies

Shefali Sabharanjak

Sahar Kamal

Ain Shams University

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Abstract 300: Protein Kinase G Positively Regulates Proteasome-mediated Degradation of Misfolded Proteins

Circulation Research, Aug 1, 2013

Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular... more Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis, evidenced by increased protein aggregates and ubiquitinated proteins. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. We sought to establish the role of protein kinase G (PKG) in these debilitating conditions, for which there is currently no cure. Methods and Results: PKG was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (GFPu) and bona fide misfolded proteins (CryABR120G), and attenuated CryABR120G overexpression-induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between PKG manipulated and the control groups were not statistically significant, but the isoelectric points of were shifted by PKG activation. In transgenic mice expressing a surrogate substrate (GFPdgn), PKG activation by sildenafil increased myocardial proteasome activities and significantly decreased myocardial GFPdgn protein levels. Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryABR120G, ubiquitin conjugates, and aberrant protein aggregates in mice with CryABR120G-based desmin-related cardiomyopathy. No discernible effect on bona fide native substrates of the ubiquitin-proteasome system was observed from PKG manipulation in vitro or in vivo. Conclusions: PKG positively regulates proteasome activities and proteasome-mediated degradation of misfolded proteins likely through posttranslational modifications to proteasome subunits. Improved protein quality control is liekly a new mechanism underlying the benefit of PKG stimulation in treating cardiac diseases. Stimulation of PKG by measures such as sildenafil administration is potentially a novel therapeutic strategy to treat cardiac proteinopathies.

Synergistic effects of gefitinib and thalidomide treatment on EGFR-TKI-sensitive and -resistant NSCLC

European Journal of Pharmacology, Aug 1, 2019

EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy i... more EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most if not all of the patients who initially have responded to EGFR-TKIs later experience progression or deterioration of the disease while still on the treatment. Drug resistance becomes inevitable due to the emergence of the second-site EGFR T790M mutation within exon 20, MET and HER2 amplification, small cell histologic transformation and rare secondary BRAF mutations. The acquired drug resistance limits the efficacy of EGFR-TKIs in patients. Thalidomide is a widely used anti-angiogenic and immunomodulatory drug with anticancer effects. The current study was aimed to explore the combined effects of gefitinib and thalidomide on NSCLC. The combination of thalidomide and gefitinib induced antiproliferative and proapoptotic effects in HCC827, PC9, and PC9GR cells. The inhibition of EGFR phosphorylation and downstream signaling was more pronounced in the thalidomide and gefitinib cotreatment group as compared with the single agent treatment groups. Further study revealed that the inhibitors of AKT, MEK/ERK, and p38 increased the antiproliferative and proapoptotic effects of the combined treatment of thalidomide and gefitinib. However, JNK inhibition moderately abrogated cell apoptosis induced by the cotreatment. In conclusion, thalidomide and gefitinib exhibit synergistic effects on both TKI-sensitive and-resistant NSCLC cells by targeting the EGFR signaling pathways, suggesting that the combination strategy is promising for the treatment of NSCLC.

Xuejun Wang

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