// Ling Ding 1 , Guikai Liang 1 , Zhangting Yao 1 , Jieqiong Zhang 1 , Ruiyang Liu 1 , Huihui Chen 1 , Yulu Zhou 1 , Honghai Wu 1 , Bo Yang 1 , Qiaojun He 1 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China Correspondence to: Qiaojun He, e-mail: qiaojunhe@zju.edu.cn Keywords: metformin, macrophage polarization, cancer metastasis, AMPKα1 Received: July 05, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.
<div>Abstract<p>Studies have pointed to a role of PARP1 in regulating gene expression through poly(ADP-ribosyl)ating, sequence-specific, DNA-binding transcription factors. However, few examples exist that link this role of PARP1 to the immunogenicity of cancer cells. Here, we report that PARP1 poly(ADP-ribosyl)ates STAT3 and subsequently promotes STAT3 dephosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacologic inhibition enhanced the transcription of PD-L1 in cancer cells, which was accompanied by the upregulation of PD-L1 protein expression, both in the cytoplasm and on the cell surface. This induction of PD-L1 was attenuated in the absence of the transcription factor STAT3. Cell-based studies indicated that PARP1 interacted directly with STAT3 and caused STAT3 poly(ADP-ribosyl)ation. STAT3′s activation of PD-L1 transcription was abolished by the overexpression of wild-type PARP1 but not mutant PARP1, which lacks catalytic activity. PARP1 downregulation or catalytic inhibition enhanced the phosphorylation of STAT3, which was reversed by the ectopic expression of wild-type PARP1 but not by mutated PARP1. An inverse correlation between PARP1 and PD-L1 was also observed in clinical ovarian cancer samples. Overall, our study revealed PARP1-mediated poly(ADP-ribosyl)ation of STAT3 as a key step in inhibiting the transcription of PD-L1, and this mechanism exists in a variety of cancer cells.</p></div>
Objective: To explore the effects of different loading swimming exercise on structures of myocardial intercalated disk of ventriculus sinister and connexin 43(Cx43) in rats, so as to provide some information for the changes of physiology and pathology by the exercise-induced injury and recuperation of cardiac muscles. Method: SD rats were randomly divided into two groups: different loading exercise group and exhaustive exercise group. In the different loading exercise group, 12-week low, moderate and high loading swimming models were carried out in rats. In the exhaustive exercise group, a single exhaustive swimming was carried out in rats. After exercise, rat's ventriculus sinister were cut off, and treated with routine procedures of transmission electron microscopy before observing the structures of intercalated disks. Immunohistochemical technique and image-analysis method were used to study the changes in distribution and content of Cx43 in myocardial tissues. Result: In control group rats ventriculus sinister showed clear structure of myocardial intercalated disks, which were composed of adhering junction, desmosome and gap junction and arranged as a flight of stairs. Cx43 was mainly distributed in intercalated disk. In low and moderate loading swimming groups the structure of intercalated disk and the distribution and content of Cx43 were similar to that of control group. In high loading swimming group the gaps of intercalated disks became wider, the contents of Cx43 decreased, and distribution of Cx43 at side-to-side junction of myocardial cells increased. In exhaustive exercise group the myocardial intercalated disks were disorganized and some regions of intercalated disks were destroyed or folded; the content of Cx43 was similar to control group at the end of exhaustive exercise, but significantly decreased with time prolongation after exhaustive exercise. Conclusion: High loading swimming and exhaustive exercise could destroy the structures of myocardial intercalated disks of ventriculus sinister, and result in degradation and change in distribution pattern of Cx43.
Diminished or lost Major Histocompatibility Complex class I (MHC-I) expression is frequently observed in tumors, which obstructs the immune recognition of tumor cells by cytotoxic T cells. Restoring MHC-I expression by promoting its transcription and improving protein stability have been promising strategies for reestablishing anti-tumor immune responses. Here, through cell-based screening models, we found that cediranib significantly upregulated MHC-I expression in tumor cells. This finding was confirmed in various non-small cell lung cancer (NSCLC) cell lines and primary patient-derived lung cancer cells. Furthermore, we discovered cediranib achieved MHC-I upregulation through transcriptional regulation. interferon regulatory factor 1 (IRF-1) was required for cediranib induced MHC-I transcription and the absence of IRF-1 eliminated this effect. Continuing our research, we found cediranib triggered STAT1 phosphorylation and promoted IRF-1 transcription subsequently, thus enhancing downstream MHC-I transcription. In vivo study, we further confirmed that cediranib increased MHC-I expression, enhanced CD8+ T cell infiltration, and improved the efficacy of anti-PD-L1 therapy. Collectively, our study demonstrated that cediranib could elevate MHC-I expression and enhance responsiveness to immune therapy, thereby providing a theoretical foundation for its potential clinical trials in combination with immunotherapy.
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