Comprehensive role of SARS-CoV-2 spike glycoprotein in regulating host signaling pathway.

Since the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, global public health and the economy have suffered unprecedented damage. Based on the increasing related literature, the characteristics and pathogenic mechanisms of the virus, and epidemiological and clinical features of the disease are being rapidly discovered. The spike glycoprotein (S protein), as a key antigen of SARS-CoV-2 for developing vaccines, antibodies, and drug targets, has been shown to play an important role in viral entry, tissue tropism, and pathogenesis. In this review, we summarize the molecular mechanisms of interaction between S protein and host factors, especially receptor-mediated viral modulation of host signaling pathways, and highlight the progression of potential therapeutic targets, prophylactic and therapeutic agents for prevention and treatment of SARS-CoV-2 infection.

An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation.

The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6. Notably, EBNA3C expression leads to reduced Bcl6 protein levels in a ubiquitin-proteasome dependent manner. Further, EBNA3C inhibits the transcriptional activity of the Bcl6 promoter through interaction with the cellular protein IRF4. Bcl6 degradation induced by EBNA3C rescued the functions of the Bcl6-targeted downstream regulatory proteins Bcl2 and CCND1, which resulted in increased proliferation and G1-S transition. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction, and raises the possibility of developing new targeted therapies against EBV-associated cancers.

WITHDRAWN: Curcumin shifts RAS-induced pro-proliferative MEK/ERK-signaling toward pro-apoptotic p38MAPK/JNK1-signaling, triggering p53 activation and apoptosis.

This article has been withdrawn by the authors. A mistake was made during the preparation of Fig 1C, NKE panel. The Western blot data shown for p-ERK1/2 and actin are not from this set, but rather a similar set of data from a different experiment. The authors apologize to the readers.

EBV Nuclear Antigen 3C Mediates Regulation of E2F6 to Inhibit E2F1 Transcription and Promote Cell Proliferation.

Epstein-Barr virus (EBV) is considered a ubiquitous herpesvirus with the ability to cause latent infection in humans worldwide. EBV-association is evidently linked to different types of human malignancies, mainly of epithelial and lymphoid origin. Of interest is the EBV nuclear antigen 3C (EBNA3C) which is critical for EBV-mediated immortalization. Recently, EBNA3C was shown to bind the E2F1 transcription regulator. The E2F transcription factors have crucial roles in various cellular functions, including cell cycle, DNA replication, DNA repair, cell mitosis, and cell fate. Specifically, E2F6, one of the unique E2F family members, is known to be a pRb-independent transcription repressor of E2F-target genes. In our current study, we explore the role of EBNA3C in regulating E2F6 activities. We observed that EBNA3C plays an important role in inducing E2F6 expression in LCLs. Our study also shows that EBNA3C physically interacts with E2F6 at its amino and carboxy terminal domains and they form a protein complex in human cells. In addition, EBNA3C stabilizes the E2F6 protein and is co-localized in the nucleus. We also demonstrated that both EBNA3C and E2F6 contribute to reduction in E2F1 transcriptional activity. Moreover, E2F1 forms a protein complex with EBNA3C and E2F6, and EBNA3C competes with E2F1 for E2F6 binding. E2F6 is also recruited by EBNA3C to the E2F1 promoter, which is critical for EBNA3C-mediated cell proliferation. These results demonstrate a critical role for E2F family members in EBV-induced malignancies, and provide new insights for targeting E2F transcription factors in EBV-associated cancers as potential therapeutic intervention strategies.

STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity.

Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy.

EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation.

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers.

Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1.

UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) has a significant contributory role in the development of three major human neoplastic or lymphoproliferative diseases: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). These diseases are associated with chromosomal instability, a hallmark of human cancer. The latency-associated nuclear antigen (LANA) encoded by KSHV plays a key role in regulating a number of cellular pathways critical for oncogenesis. KSHV LANA alone can induce the development of B-cell hyperplasia and lymphoma in mice expressing LANA. LANA also induces chromosomal instability, thus promoting oncogenesis. However, the precise mechanism underlying LANA-mediated chromosomal instability remains uncharted. Here we report that LANA promoted the induction of chromosomal instability and the formation of micronuclei and multinucleation through its interaction with one of the critical spindle checkpoint proteins, Bub1, and the resulting degradation of Bub1. This interaction occurs through the Knl and kinase domains of Bub1, identified as important for stability and degradation. These results suggest that LANA can dysregulate Bub1 activity, which leads to aberrant chromosome replication and aneuploidy, thus contributing to KSHV-mediated oncogenesis. IMPORTANCE: This work represents the first set of results identifying a novel mechanism by which LANA, a latency-associated antigen encoded by KSHV, can induce the degradation of Bub1, a spindle checkpoint protein that is important for spindle checkpoint signaling and chromosome segregation. The downregulation of Bub1 mediated by LANA resulted in chromosomal instability, a hallmark of cancer. We further investigated the specific domains of Bub1 that are required for the interaction between LANA and Bub1. The results demonstrated that the Knl and kinase domains of Bub1 are required for the interaction between LANA and Bub1. In addition, we also investigated the mechanism by which LANA promoted Bub1 degradation. Our results showed that LANA interacted physically with the anaphase-promoting complex (APC/C), thus promoting the degradation of Bub1 in a ubiquitin-dependent process.

Kaposi's sarcoma-associated herpesvirus-encoded LANA contributes to viral latent replication by activating phosphorylation of survivin.

UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV-infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells. IMPORTANCE: This work represents a report of KSHV latent protein LANA and its interactions with AK-B leading to induction of phosphorylation of the oncoprotein survivin at residue T34. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases. This leads to an increase in viral copy number in KSHV-infected B cells. These studies support a role for LANA in regulating KSHV replication through posttranslation modification in KSHV-infected B cells.

Epstein-Barr virus essential antigen EBNA3C attenuates H2AX expression.

Epstein-Barr virus (EBV) latent antigen EBNA3C is implicated in B-cell immortalization and linked to several B-cell malignancies. Deregulation of H2AX can induce genomic instability with increased chromosomal aberrations, which ultimately leads to tumorigenesis. Here we demonstrated that EBNA3C can attenuate H2AX expression at the transcript and protein levels. A reduction of total H2AX levels was clearly observed upon infection of primary B cells with wild-type EBV but not with EBNA3C knockout recombinant EBV. H2AX also interacted with EBNA3C through its N-terminal domain (residues 1 to 100). Furthermore, H2AX mutated at Ser139 failed to interact with EBNA3C. Luciferase-based reporter assays also revealed that the binding domain of EBNA3C is sufficient for transcriptional inhibition of the H2AX promoter. EBNA3C also facilitated H2AX degradation through recruitment of components of the ubiquitin proteasome pathway. We further demonstrated that knockdown of H2AX in lymphoblastoid cell lines (LCLs) led to the upregulation of the Bub1 oncoprotein and downregulated expression of p53. Overall, our study provides additional insights into EBV-associated B-cell lymphomas, which are linked to the regulation of the DNA damage response system in infected cells. The importance of these insights are as follows: (i) EBNA3C downregulates H2AX expression at the protein and transcript levels in epithelial cells, B cells, and EBV-transformed LCLs, (ii) EBNA3C binds with wild-type H2AX but not with the Ser139 mutant of H2AX, (iii) the N terminus (residues 1 to 100) of EBNA3C is critical for binding to H2AX, (iv) localization of H2AX is predominantly nuclear in the presence of EBNA3C, and (v) H2AX knocked down in LCLs led to enhanced expression of Bub1 and downregulation of the tumor suppressor p53, which are both important for driving the oncogenic process.

Inhibition of KAP1 enhances hypoxia-induced Kaposi's sarcoma-associated herpesvirus reactivation through RBP-Jκ.

UNLABELLED: Hypoxia-inducible factor 1α (HIF-1α) has been frequently implicated in many cancers as well as viral pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several human malignancies. It can stabilize HIF-1α during latent infection and undergoes lytic replication in response to hypoxic stress. However, the mechanism by which KSHV controls its latent and lytic life cycle through the deregulation of HIF-1α is not fully understood. Our previous studies showed that the hypoxia-sensitive chromatin remodeler KAP1 was targeted by the KSHV-encoded latency-associated nuclear antigen (LANA) to repress expression of the major lytic replication and transcriptional activator (RTA). Here we further report that an RNA interference-based knockdown of KAP1 in KSHV-infected primary effusion lymphoma (PEL) cells disrupted viral episome stability and abrogated sub-G1/G1 arrest of the cell cycle while increasing the efficiency of KSHV lytic reactivation by hypoxia or using the chemical 12-O-tetradecanoylphorbol-13-acetate (TPA) or sodium butyrate (NaB). Moreover, KSHV genome-wide screening revealed that four hypoxia-responsive clusters have a high concurrence of both RBP-Jκ and HIF-1α binding sites (RBS+HRE) within the same gene promoter and are tightly associated with KAP1. Inhibition of KAP1 greatly enhanced the association of RBP-Jκ with the HIF-1α complex for driving RTA expression not only in normoxia but also in hypoxia. These results suggest that both KAP1 and the concurrence of RBS+HRE within the RTA promoter are essential for KSHV latency and hypoxia-induced lytic reactivation. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV), a DNA tumor virus, is an etiological agent linked to several human malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). HIF-1α, a key hypoxia-inducible factor, is frequently elevated in KSHV latently infected tumor cells and contributes to KSHV lytic replication in hypoxia. The molecular mechanisms of how KSHV controls the latent and lytic life cycle through deregulating HIF-1α remain unclear. In this study, we found that inhibition of hypoxia-sensitive chromatin remodeler KAP1 in KSHV-infected PEL cells leads to a loss of viral genome and increases its sensitivity to hypoxic stress, leading to KSHV lytic reactivation. Importantly, we also found that four hypoxia-responsive clusters within the KSHV genome contain a high concurrence of RBP-Jκ (a key cellular regulator involved in Notch signaling) and HIF-1α binding sites. These sites are also tightly associated with KAP1. This discovery implies that KAP1, RBP-Jκ, and HIF-1α play an essential role in KSHV pathogenesis through subtle cross talk which is dependent on the oxygen levels in the infected cells.

IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA to inhibit MHC II presentation.

Peptides presentation to T cells by MHC class II molecules is of importance in initiation of immune response to a pathogen. The level of MHC II expression directly influences T lymphocyte activation and is often targeted by various viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) encoded LANA is known to evade MHC class I peptide processing, however, the effect of LANA on MHC class II remains unclear. Here, we report that LANA down-regulates MHC II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA) promoter pIII and pIV in a dose-dependent manner. Strikingly, although LANA knockdown efficiently disrupts the inhibition of CIITA transcripts from its pIII and pIV promoter region, the expression of HLA-DQß but no other MHC II molecules was significantly restored. Moreover, we revealed that the presentation of HLA-DQß enhanced by LANA knockdown did not help LANA-specific CD4+ T cell recognition of PEL cells, and the inhibition of CIITA by LANA is independent of IL-4 or IFN-γ signaling but dependent on the direct interaction of LANA with IRF-4 (an activator of both the pIII and pIV CIITA promoters). This interaction dramatically blocked the DNA-binding ability of IRF-4 on both pIII and pIV promoters. Thus, our data implies that LANA can evade MHC II presentation and suppress CIITA transcription to provide a unique strategy of KSHV escape from immune surveillance by cytotoxic T cells.

The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8.

Epstein-Barr virus (EBV) is linked to a broad spectrum of B-cell malignancies. EBV nuclear antigen 3C (EBNA3C) is an encoded latent antigen required for growth transformation of primary human B-lymphocytes. Interferon regulatory factor 4 (IRF4) and 8 (IRF8) are transcription factors of the IRF family that regulate diverse functions in B cell development. IRF4 is an oncoprotein with anti-apoptotic properties and IRF8 functions as a regulator of apoptosis and tumor suppressor in many hematopoietic malignancies. We now demonstrate that EBNA3C can contribute to B-cell transformation by modulating the molecular interplay between cellular IRF4 and IRF8. We show that EBNA3C physically interacts with IRF4 and IRF8 with its N-terminal domain in vitro and forms a molecular complex in cells. We identified the Spi-1/B motif of IRF4 as critical for EBNA3C interaction. We also demonstrated that EBNA3C can stabilize IRF4, which leads to downregulation of IRF8 by enhancing its proteasome-mediated degradation. Further, si-RNA mediated knock-down of endogenous IRF4 results in a substantial reduction in proliferation of EBV-transformed lymphoblastoid cell lines (LCLs), as well as augmentation of DNA damage-induced apoptosis. IRF4 knockdown also showed reduced expression of its targeted downstream signalling proteins which include CDK6, Cyclin B1 and c-Myc all critical for cell proliferation. These studies provide novel insights into the contribution of EBNA3C to EBV-mediated B-cell transformation through regulation of IRF4 and IRF8 and add another molecular link to the mechanisms by which EBV dysregulates cellular activities, increasing the potential for therapeutic intervention against EBV-associated cancers.

EBNA3C-mediated regulation of aurora kinase B contributes to Epstein-Barr virus-induced B-cell proliferation through modulation of the activities of the retinoblastoma protein and apoptotic caspases.

Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that is implicated in several human malignancies, including Burkitt's lymphoma (BL), posttransplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma (NPC), and AIDS-associated lymphomas. Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential EBV latent antigens, can induce mammalian cell cycle progression through its interaction with cell cycle regulators. Aurora kinase B (AK-B) is important for cell division, and deregulation of AK-B is associated with aneuploidy, incomplete mitotic exit, and cell death. Our present study shows that EBNA3C contributes to upregulation of AK-B transcript levels by enhancing the activity of its promoter. Further, EBNA3C also increased the stability of the AK-B protein, and the presence of EBNA3C leads to reduced ubiquitination of AK-B. Importantly, EBNA3C in association with wild-type AK-B but not with its kinase-dead mutant led to enhanced cell proliferation, and AK-B knockdown can induce nuclear blebbing and cell death. This phenomenon was rescued in the presence of EBNA3C. Knockdown of AK-B resulted in activation of caspase 3 and caspase 9, along with poly(ADP-ribose) polymerase 1 (PARP1) cleavage, which is known to be an important contributor to apoptotic signaling. Importantly, EBNA3C failed to stabilize the kinase-dead mutant of AK-B compared to wild-type AK-B, which suggests a role for the kinase domain in AK-B stabilization and downstream phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). This study demonstrates the functional relevance of AK-B kinase activity in EBNA3C-regulated B-cell proliferation and apoptosis.

Drug repurposing for cancer.

In the dynamic landscape of cancer therapeutics, the innovative strategy of drug repurposing emerges as a transformative paradigm, heralding a new era in the fight against malignancies. This book chapter aims to embark on the comprehension of the strategic deployment of approved drugs for repurposing and the meticulous journey of drug repurposing from earlier times to the current era. Moreover, the chapter underscores the multifaceted and complex nature of cancer biology, and the evolving field of cancer drug therapeutics while emphasizing the mandate of drug repurposing to advance cancer therapeutics. Importantly, the narrative explores the latest tools, technologies, and cutting-edge methodologies including high-throughput screening, omics technologies, and artificial intelligence-driven approaches, for shaping and accelerating the pace of drug repurposing to uncover novel cancer therapeutic avenues. The chapter critically assesses the breakthroughs, expanding the repertoire of repurposing drug candidates in cancer, and their major categories. Another focal point of this book chapter is that it addresses the emergence of combination therapies involving repurposed drugs, reflecting a shift towards personalized and synergistic treatment approaches. The expert analysis delves into the intricacies of combinatorial regimens, elucidating their potential to target heterogeneous cancer populations and overcome resistance mechanisms, thereby enhancing treatment efficacy. Therefore, this chapter provides in-depth insights into the potential of repurposing towards bringing the much-needed big leap in the field of cancer therapeutics.

Drug repurposing for neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.

Investigation of biochemical, enzymatic, and metagenomic profiles of garbage enzymes and its application in dumping site leachate treatment.

The current article focuses on the preparation and characterization of garbage enzyme (GE) and explores its applications in treating leachate. GE is prepared from fruit and vegetable wastes and characterized via analysis of metabolites, carbohydrates, proteins, antioxidants, and enzymatic activities. This study extends our understanding of GE by reporting the presence of various metabolites. Moreover, a metagenomic analysis of GE is presented, shedding light on the microbial diversity. Firmicutes emerged as the dominant phylum, surpassing other phyla, including Proteobacteria and Actinobacteria. When exploring the potential for leachate treatment, the results indicate that vegetable GE shows 68% reduction in COD (chemical oxygen demand) and 39% reduction in ammoniacal nitrogen. Similarly, non-citrus GE also showed 64% reduction in COD and a 37% reduction in ammoniacal nitrogen, followed by citrus GE with a 33% reduction in COD and a 34% reduction in ammoniacal nitrogen compared to the control.

Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways.

Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate RET as a promising and potential target for MTC therapy.

Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis.

The Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential latent antigens for Epstein-Barr virus (EBV)-induced immortalization of primary human B lymphocytes in vitro, has been implicated in regulating cell proliferation and anti-apoptosis via interaction with several cellular and viral factors. Gemin3 (also named DDX20 or DP103) is a member of DEAD RNA helicase family which exhibits diverse cellular functions including DNA transcription, recombination and repair, and RNA metabolism. Gemin3 was initially identified as a binding partner to EBNA2 and EBNA3C. However, the mechanism by which EBNA3C regulates Gemin3 function remains unclear. Here, we report that EBNA3C directly interacts with Gemin3 through its C-terminal domains. This interaction results in increased stability of Gemin3 and its accumulation in both B lymphoma cells and EBV transformed lymphoblastoid cell lines (LCLs). Moreover, EBNA3C promotes formation of a complex with p53 and Gemin3 which blocks the DNA-binding affinity of p53. Small hairpin RNA based knockdown of Gemin3 in B lymphoma or LCL cells remarkably attenuates the ability of EBNA3C to inhibit the transcription activity of p53 on its downstream genes p21 and Bax, as well as apoptosis. These findings provide the first evidence that Gemin3 may be a common target of oncogenic viruses for driving cell proliferation and anti-apoptotic activities.

Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics.

Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.

Curcumin enhances the efficacy of chemotherapy by tailoring p65NFκB-p300 cross-talk in favor of p53-p300 in breast cancer.

Breast cancer cells often develop multiple mechanisms of drug resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. High constitutive activation of NFκB has been found in different cancers, creating an environment conducive for chemotherapeutic resistance. Here we report that doxorubicin-induced SMAR1-dependent transcriptional repression and SMAR1-independent degradation of IkBα resulted in nuclear translocation of p65NFκB and its association with p300 histone acetylase and subsequent transcription of Bcl-2 to impart protective response in drug-resistant cells. Consistently SMAR1-silenced drug-resistant cells exhibited IkBα-mediated inhibition of p65NFκB and induction of p53-dependent apoptosis. Interestingly, curcumin pretreatment of drug-resistant cells alleviated SMAR1-mediated p65NFκB activation and hence restored doxorubicin sensitivity. Under such anti-survival condition, induction of p53-p300 cross-talk enhanced the transcriptional activity of p53 and intrinsic death cascade. Importantly, promyelocyte leukemia-mediated SMAR1 sequestration that relieved the repression of apoptosis-inducing genes was indispensable for such chemo-sensitizing ability of curcumin. A simultaneous decrease in drug-induced systemic toxicity by curcumin might also have enhanced the efficacy of doxorubicin by improving the intrinsic defense machineries of the tumor-bearer. Overall, the findings of this preclinical study clearly demonstrate the effectiveness of curcumin to combat doxorubicin-resistance. We, therefore, suggest curcumin as a potent chemo-sensitizer to improve the therapeutic index of this widely used anti-cancer drug. Taken together, these results suggest that curcumin can be developed into an adjuvant chemotherapeutic drug.