The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune escape.Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune response.Currently,some FDA-approved monoclonal antibodies are clinicallyused for cancer treatment by blocking PD-1/PD-L1 interaction.Despite notable treatment outcomes,some pa-tients show poor drug response.Exosomal PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface PD-L1.To enhance therapeutic response,inhibition of exosomal PD-L1 is required.Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors.Im-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 expression.Therefore,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider-ation.In this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.

Association between prolactin/testosterone ratio and breast cancer in Chinese women

To the Editor:Breast cancer is a prevalent malignant tumor and ranks as the second leading cause of cancer-related deaths globally.^([1])The breast is the target organ of some endocrine hormones,which regulate its growth and development.Aside from estrogen and progesterone,the relationship among prolactin,androgen,and breast cancer has recently garnered increasing attention.

A critical role of the thioredoxin domain containing protein 5(TXNDC5) in redox homeostasis and cancer development

Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase(PDI)family.As a critical member of the PDI family,thioredoxin domain containing protein 5(TXNDC5)assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions.Interestingly,TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer.In this review,we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development.Findings of TXNDC5 in the activation of intracellular signaling pathways,stimulation of cell growth&proliferation,facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed.These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

Beclin 1-Vps34 complex architecture： Understanding the nuts and bolts of therapeutic targets

Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin I-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.

Epigenetic regulation of prostate cancer

Prostate cancer is(PCa)the second leading cause of cancer death in males in the United State,with 174,650 new cases and 31,620 deaths estimated in 2019.It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression.EZH2(enhancer of zeste homolog 2),the catalytic subunit of the Polycomb Repressive Complex(PRC2)responsible for H3K27me3 and gene repression,has been identified as a promising target in PCa.In addition,overexpression of other epigenetic regulators such as DNA methyltransferases(DNMT)is also observed in PCa.These epigenetic regulators undergo extensive post-translational modifications,in particular,phosphorylation.AKT,CDKs,PLK1,PKA,ATR and DNA-PK are the established kinases responsible for phosphorylation of various epigenetic regulators.

Control of CD4^(+) T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase

CD4^(+)T cells,particularly IL-17-secreting helper CD4^(+)T cells,play a central role in the inflammatory processes underlying autoimmune disorders.Eukaryotic Elongation Factor 2 Kinase(eEF2K)is pivotal in CD8^(+)T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension.However,its specific immunological role in CD4^(+)T cell activities and related inflammatory diseases remains elusive.Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4^(+)T cells,impairs their ability to secrete cytokines.Notably,this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17,fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4^(+)T cells.Furthermore,the absence of eEF2K in CD4^(+)T cells is linked to increased metabolic activity and mitochondrial bioenergetics.We have shown that eEF2K regulates mitochondrial function and CD4^(+)T cell activity through the upregulation of the transcription factor,signal transducer and activator of transcription 3(STAT3).Crucially,the deficiency of eEF2K exacerbates the severity of inflammation-related diseases,including rheumatoid arthritis,multiple sclerosis,and ulcerative colitis.Strikingly,the use of C188-9,a small molecule targeting STAT3,mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout(KO)CD4^(+)T cells.These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4^(+)T cells and its indispensable involvement in inflammation-related diseases.Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.

Metabolic reprogramming in tumors:Contributions of the tumor microenvironment

The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment,and prepare for metastasis.Qualitatively,the fundamental biochemistry of cancer cells is generally the same as in the untransformed cells,but the cancer cells produce a local environment,the TME,that is hostile to the stromal cells,and compete for nutrients.In order to proliferate,cells need sufficient nutrients,either those that cannot be made by the cells themselves,or must be made from simpler precursors.However,in solid tumors,the nutrient supply is often limiting given the potential for rapid proliferation,and the poor quality of the vasculature.Thus,cancer cells may employ a variety of strategies to obtain nutrients for survival,growth and metastasis.Although much has been learned using established cell lines in standard culture conditions,it is becoming clear from in vivo metabolic studies that this can also be misleading,and which nutrients are used for energy production versus building blocks for synthesis of macromolecules can vary greatly from tumor to tumor,and even within the same tumor.Here we review the operation of metabolic networks,and how recent understanding of nutrient supply in the TME and utilization are being revealed using stable isotope tracers in vivo as well as in vitro.

IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas

The insulin-like growth factor 1 receptor(IGF-1R)governs several signaling pathways for cell proliferation,survival,and antiapoptosis.Thus,targeting IGF-1R appears as a reasonable rationale for tumor treatment.However,clinical studies showed that inhibition of IGF-1R has very limited efficacy due to the development of resistance to IGF-1R blockade in tumor cells.Here,we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors(BMS-754807 and GSK1838705A)stimulates p70 KDa ribosomal protein S6 kinase 1(p70S6K1)activation,a well-known kinase signaling for cell survival.We also found that p70S6K1 activation by IGF-1R inhibition is independent of K-Ras and PIK3CA mutations that frequently occur in colon cancer.Besides the increased p70S6K1 phosphorylation,the phosphorylation of mitogen-activated protein kinase kinase 1 and 2(MEK1/2)was elevated in the cells treated with BMS-754807.Interestingly,the increases in MEK1/2 and p70S6K1 phosphorylation were also observed when cells were subjected to the treatment of AKT inhibitor or genetic knockdown of AKT2 but not AKT1,suggesting that AKT2 inhibition stimulates MEK1/2 phosphorylation to activate p70S6K1.Conversely,inhibition of MEK1/2 by MEK1/2 inhibitor(U0126)or knockdown of MEK1 and MEK2 by corresponding mek1 and mek2 siRNA enhanced AKT phosphorylation,indicating mutual inhibition between AKT and MEK.Furthermore,the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo.Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival,providing a new strategy for colorectal cancer therapeutics.

喉癌患者癌组织与癌旁正常组织之间蛋白磷酸酶2A及其相关分子标志物表达水平的比较研究（英文）

目的:探讨喉癌患者组织样本中蛋白磷酸酶2A及其相关蛋白在癌组织与癌旁组织之间的表达差异,建立可用于临床进行喉癌患者预后分层的多指标预测体系。创新点:以蛋白磷酸酶2A为核心,探讨系列肿瘤转移相关指标参与喉癌发生发展的分子机制。方法:收集2012~2015年间浙江大学医学院附属第二医院耳鼻咽喉科28例喉鳞状细胞癌患者的临床组织样本,提取总蛋白后进行免疫印迹分析。结论:与癌旁正常组织相比,喉癌组织中phosphoPP2A/C(Y307)、α4、CIP2A、Akt、ezrin、phosphoezrin(T567)、14-3-3以及FAK蛋白水平均显著升高,而phospho-Akt(T308)蛋白水平则显著降低。

The Nobel Prize in Chemistry 2015:Exciting discoveries in DNA repair by Aziz Sancar

INTRODUCTION On October 7,2015,the Nobel Prize in Chemistry for 2015was awarded to three deserving scientists for their pioneering research on DNA repair.Tomas Lindahl was recognized for studies that uncovered the inherent instability of DNA as well as the mechanism of the base excision repair pathway,Paul Modrich for characterization of the mismatch