Role of MST1 in the regulation of autophagy and mitophagy: implications for aging-related diseases

As a key mechanism to maintain cellular homeostasis under stress conditions, autophagy/mitophagy is related to the occurrence of metabolic disorders, neurodegenerative diseases, cancer, and other aging-related diseases, but the relevant signal pathways regulating autophagy have not been clarified. Mammalian sterile 20-like kinase 1 (MST1) is a central regulatory protein of many metabolic pathways involved in the pathophysiological processes of aging and aging-related diseases and has become a critical integrator affecting autophagic signaling. Recent studies show that MST1 not only suppresses autophagy through directly phosphorylating Beclin-1 and/or inhibiting the protein expression of silent information regulator 1 (SIRT1) in the cytoplasm, but also inhibits BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3)–, FUN14 domain containing 1 (FUNDC1)–, and Parkin (Parkinson protein 2)–mediated mitophagy by interacting with factors such as Ras association domain family 1A (RASSF1A). Indeed, a common pharmacological strategy for anti-aging is to induce autophagy/mitophagy through MST1 inhibition. This article reviews the role and mechanism of MST1 in regulating autophagy during aging, to provide evidence for the development of drugs targeting MST1. (AU)

Relation of beclin-1 and bcl-2 expressions with pathological parameters and prognosis in clear cell renal cell carcinomas

Introduction: The most common type of renal cancers is the clear cell renal cell carcinoma (CCRCC) and 98% of CCRCCshave a loss of sequence in the short arm of chromosome 3 by deletion or translocation. Programmed cell death; another possiblemechanism of tumorigenesis, comprises two separate components: apoptosis and autophagy. This study aims to show the relation between the prognostic parameters and survival, and Beclin-1, as the representative marker of autophagy, and Bcl-2 as therepresentative marker of apoptosis in CCRCC patients. In this study, we aimed to determine if Beclin-1 and Bcl-2 expressionlevels can provide any prognostic information about CCRCC patients.Methods: We examined a total of 84 patients who underwent partial or radical nephrectomy and were diagnosed as havingCCRCC between January 2008 and December 2015. Immunohistochemical staining was performed, the evaluation was forBeclin-1 and Bcl-2 semi-quantitative, and based on the percentage of positively stained cells (proportion) and staining intensity.Results: There was only a statistical significance between Beclin-1 expression and age (r:-0.274; p=0.012; p <0.05). There wasa marginal significance between ISUP grade and Beclin-1 (p=0.051). The relation of Bcl-2 expression with the ISUP grade,recurrence, metastasis, and mortality revealed statistical significance (p=0.001, p=0.019, p=0.009, p=0.013, respectively). TheISUP grade and the Bcl-2 expression revealed statistical significance on multivariate analysis ( HR 7.453, 95% CI: 1.935-28.713,p=0.004). The 5-year and 10-year tumor recurrences rates were lower in Bcl-2 positive group, and Bcl-2 positive group experienced longer disease free and overall survival...(AU)

CIP2A silencing alleviates doxorubicin resistance in MCF7/ADR cells through activating PP2A and autophagy

Background Cancerous inhibitor of protein phosphatase 2A (CIP2A) plays a critical role in the pathogenesis of various types of cancer. Here, we investigated whether manipulating CIP2A abundance could enhance the treatment effects of doxorubicin in MCF-7/ADR cells. Methods CIP2A silencing was achieved by specific siRNAs. Proliferation of breast cancer cell line MCF-7/ADR under effective doxorubicin concentrations after CIP2A silencing was examined by MTT assay. Wound healing assay was performed to quantify cell migration and caspase-3/-7 activities were measured for assessing the extent of apoptosis. Results First, our data confirmed that MCF-7/ADR cell proliferation was suppressed by doxorubicin in a dose-dependent manner. Additionally, knocking down of CIP2A could further decrease MCF-7 cell proliferation and migration, even in the presence of doxorubicin. Mechanistically, we have found that CIP2A silencing promoted cell apoptosis relative to doxorubicin alone or vehicle control groups. Lastly, phosphatase2A (PP2A) activity was potentiated and the autophagy markers, LC3B and Beclin1, were upregulated after knocking down CIP2A. Conclusion Our findings support the potential benefits of using CIP2A inhibitor as a therapeutic agent to treat doxorubicin-resistant breast cancer (AU)

Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients

Autophagy was shown to modulate inflammation in immune cells. This study was designed to evaluate the association between autophagy and inflammation in peripheral blood mononuclear cells (PBMCs) of type 2 diabetic (T2D) and non-diabetic (ND) subjects. The autophagy markers were measured by real-time PCR and western blot. The gene expression of pro- and anti-inflammatory cytokines was assessed by real-time PCR. Reduced transcription of BECN1 and LAMP2 and unchanged expression of MAP1LC3B and ATG5 were observed in PBMCs of T2D patients. Decreased LC3B-II and increased p62/SQSTM1 levels were found in PBMCs of diabetic patients. The p-mTOR level was higher in PBMCs of diabetic patients. An increase in both IL-1Beta and TNF-alfa gene expression, along with a decrease in the expression of IL-10, was observed in PBMCs of T2D patients. TNF-α mRNA expression was inversely correlated with the mRNA expression of BECN1 and LAMP2. TNF-alfa and IL-1Beta expression were negatively correlated with the protein levels of LC3B-II. TNF-alfa and IL-1Beta expression had also a positive correlation with protein level of p62. IL-10 mRNA expression was positively correlated with the mRNA expression of BECN1 and LAMP2 and protein levels of LC3B-II and negatively correlated with protein level of p62. In addition, p-mTOR level was positively correlated with IL-1Beta and TNF-alfa mRNA expression. The results revealed a reduced autophagy in PBMCs of T2D patients that is liked with an enhanced inflammation. The suppression of autophagy in PBMCs of diabetic patients may be associated with the activation of the mTOR signaling