An open access journal of molecular signaling: a critical need at a critical time

Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. This area also focuses on defining the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological as well as pathological conditions. Therefore, rapid publication of results from these endeavors and, more importantly, free access to such publications can truly accelerate the progress in this field leading to the development of novel targeted drugs. With this goal in mind, Journal of Molecular Signaling, a journal fully devoted to open access publishing of rigorously peer-reviewed quality manuscripts in the molecular signaling area of research, is being launched. The focus, significance, and, the open access model of publishing of Journal of Molecular Signaling are discussed

Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol.

peer reviewedCancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the "Warburg effect". Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed for cell duplication. Autophagy, a macromolecular degradation process, limits cell mass accumulation and opposes to cell proliferation as well as to cell migration. Cancer cells corrupt cancer-associated fibroblasts to release pro-inflammatory cytokines, which in turn promote glycolysis and support the metastatic dissemination of cancer cells. In mimicking in vitro this condition, we show that IL-6 promotes ovarian cancer cell migration only in the presence of glycolysis. The nutraceutical resveratrol (RV) counteracts glucose uptake and metabolism, reduces the production of reactive oxygen species consequent to excessive glycolysis, rescues the mitochondrial functional activity, and stimulates autophagy. Consistently, the lack of glucose as well as its metabolically inert analogue 2-deoxy-D-glucose (2-DG), which inhibits hexokinase 2 (HK2), trigger autophagy through mTOR inhibition, and prevents IL-6-induced cell migration. Of clinical relevance, bioinformatic analysis of The Cancer Genome Atlas dataset revealed that ovarian cancer patients bearing mutated TP53 with low expression of glycolytic markers and IL-6 receptor, together with markers of active autophagy, display a longer overall survival and are more responsive to platinum therapy. Taken together, our findings demonstrate that RV can counteract IL-6-promoted ovarian cancer progression by rescuing glycolysis-mediated inhibition of autophagy and support the view that targeting Warburg metabolism can be an effective strategy to limit the risk for cancer metastasis

Decoding the Oncogenic Signals from the Long Non-Coding RNAs

Cancer is one of the leading causes of death worldwide. Multifactorial etiology of cancer and tumor heterogeneity are the two most acute challenges in existing diagnostic and therapeutic strategies for cancer. An effective precision cancer medicine strategy to overcome these challenges requires a clear understanding of the transcriptomic landscape of cancer cells. Recent innovative breakthroughs in high-throughput sequencing technologies have identified the oncogenic or tumor-suppressor role of several long non-coding RNAs (lncRNAs). LncRNAs have been characterized as regulating various signaling cascades which are involved in the pathobiology of cancer. They modulate cancer cell survival, proliferation, metabolism, invasive metastasis, stemness, and therapy-resistance through their interactions with specific sets of proteins, miRNAs and other non-coding RNAs, mRNAs, or DNAs in cells. By virtue of their ability to regulate multiple sets of genes and their cognate signaling pathways, lncRNAs are emerging as potential candidates for diagnostic, prognostic, and therapeutic targets. This review is focused on providing insight into the mechanisms by which different lncRNAs play a critical role in cancer growth, and their potential role in cancer diagnosis, prognosis, and therapy

Mitogenic Signaling by the gep Oncogene Involves the Upregulation of S-Phase Kinase-Associated Protein 2

The gep oncogene, defined by the activated mutant of the α-subunit of the G protein G12 (Gα12Q229L or Gα12QL), potently stimulates the proliferation of many different cell types in addition to inducing neoplastic transformation of several fibroblast cell lines. While it has been demonstrated that Gα12QL accelerates G1- to S-phase cell cycle progression, the precise mechanism through which Gα12 communicates to cell cycle machinery is largely unknown. In the present study, we report that the activated—mutational as well as receptor-mediated—Gα12 transmits its proliferative signals to cell cycle machinery by modulating the levels of the S-phase kinase-associated protein 2 (Skp2), an E3 ubiquitin ligase, involved in the regulation of the cyclin-dependent kinase inhibitor (CKI), p27Kip1. Our results show that the expression of Gα12QL leads to an increase in the levels of Skp2 with a correlatable decrease in p27Kip1 levels and subsequent increase in the activities of specific CDKs. By demonstrating that the transient expression of Gα12QL induces an increase in Skp2 levels with resultant downregulation of p27Kip1 in both NIH3T3 and human astrocytoma 1321N1 cells, we establish here that the effect of Gα12 on Skp2/p27Kip1 is cell type independent. In addition, we demonstrate that LPA-stimulated proliferation and changes in Skp2 and p27Kip1 levels in 1321N1 cells could be inhibited by the expression of a dominant-negative mutant of Gα12, thereby pointing to the critical role of Gα12 in LPA-mediated mitogenic signaling. Our findings also indicate that LPA as well as Gα12-mediated upregulation of Skp2 requires a yet to be characterized mechanism involving JNK. Since Skp2 has been identified as an oncogene, and it is overexpressed in many cancers, our results presented here describe for the first time that Skp2 is a novel target in the cell cycle machinery through which Gα12 and its cognate receptors transmit their oncogenic signals

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα(12)

The GTPase-deficient, activated mutant of Gα(12) (Gα(12)Q229L, or Gα(12)QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor α (PDGFRα) in Gα(12)-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Gα(12)QL stimulates the functional expression of PDGFRα and demonstrate that the expression of PDGFRα by Gα(12)QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Gα(12)QL or the activation of Gα(12-)coupled receptors stimulates the expression of PDGFRα in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRα in Gα(12)QL-transformed cells. Analysis of the functional consequences of the Gα(12)-PDGFRα signaling axis indicates that Gα(12) stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Gα(12)QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRα- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRα-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Gα(12)QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRα attenuated Gα(12)-mediated neoplastic transformation of NIH 3T3 cells

Signaling by LncRNAs: Structure, Cellular Homeostasis, and Disease Pathology

The cellular signaling network involves co-ordinated regulation of numerous signaling molecules that aid the maintenance of cellular as well as organismal homeostasis. Aberrant signaling plays a major role in the pathophysiology of many diseases. Recent studies have unraveled the superfamily of long non-coding RNAs (lncRNAs) as critical signaling nodes in diverse signaling networks. Defective signaling by lncRNAs is emerging as a causative factor underlying the pathophysiology of many diseases. LncRNAs have been shown to be involved in the multiplexed regulation of diverse pathways through both genetic and epigenetic mechanisms. They can serve as decoys, guides, scaffolds, and effector molecules to regulate cell signaling. In comparison with the other classes of RNAs, lncRNAs possess unique structural modifications that contribute to their diversity in modes of action within the nucleus and cytoplasm. In this review, we summarize the structure and function of lncRNAs as well as their vivid mechanisms of action. Further, we provide insights into the role of lncRNAs in the pathogenesis of four major disease paradigms, namely cardiovascular diseases, neurological disorders, cancers, and the metabolic disease, diabetes mellitus. This review serves as a succinct treatise that could open windows to investigate the role of lncRNAs as novel therapeutic targets.N

The second annual conference of International ovarian cancer consortium and the symposium on tumor microenvironment and therapeutic resistance

The second Annual Meeting of the International Ovarian Cancer Consortium (IOCC) was held in conjunction with the Symposium on Tumor Microenvironment and Therapeutic Resistance at the Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, and USA. A brief welcoming event along with the banquet on Aug 16th was followed by the eight thematic scientific sessions from August 16 to 18, 2015. Forty-three lectures, organized in eight sessions, were discussed in front of an audience of more than hundred attendees. Emphasis was put on oncogene signaling in cancer genesis and progression, new approaches in Precision Medicine and therapy of ovarian cancer, the role of tumor microenvironment in carcinogenesis, and preventive/curative potential of natural products. In this meeting-report, we highlight the findings and the perspectives in cancer biology and therapeutic strategies that emerged during the conference

Lysophosphatidic Acid Stimulates the Proliferation of Ovarian Cancer Cells via the gep Proto-Oncogene Gα12

Lysophosphatidic acid (LPA), an agonist that activates specific G protein–coupled receptors, is present at an elevated concentration in the serum and ascitic fluid of ovarian cancer patients. Although the increased levels of LPA have been linked to the genesis and progression of different cancers including ovarian carcinomas, the specific signaling conduit utilized by LPA in promoting different aspects of oncogenic growth has not been identified. Here, we show that LPA stimulates both migration and proliferation of ovarian cancer cells. Using multiple approaches, we demonstrate that the stimulation of ovarian cancer cells with LPA results in a robust and statistically significant proliferative response. Our results also indicate that Gα12, the gep proto-oncogene, which can be stimulated by LPA via specific LPA receptors, is overtly activated in a large array of ovarian cancer cells. We further establish that LPA stimulates the rapid activation of Gα12 in SKOV-3 cells and the expression of CT12, an inhibitory minigene of Gα12 that disrupts LPAR-Gα12 interaction and potently inhibits such activation. Using this inhibitory molecule as well as the shRNA approach, we show that the inhibition of Gα12 or silencing of its expression drastically and significantly attenuates LPA-mediated proliferation of ovarian cancer cell lines such as SKOV3, Hey, and OVCAR-3. Together with our findings that the silencing of Gα12 does not have any significant effect on LPA-mediated migratory response of SKOV3 cells, our results point to a critical role for LPA-LPAR-Gα12 signaling in ovarian cancer cell proliferation and not in migration. Thus, results presented here for the first time demonstrate that the gep proto-oncogene forms a specific node in LPA-LPAR–mediated mitogenic signaling in ovarian cancer cells