scholarly journals Addressing cancer signal transduction pathways with antisense and siRNA oligonucleotides

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Rudolph L Juliano
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Cancer Therapeutics ◽  
Future Research ◽  
Signal Transduction Pathways ◽  
Ras Signaling ◽  
Cancer Signaling ◽  
Challenges And Opportunities ◽  
Cancer Signal Transduction

Abstract Signal transduction pathways play key roles in the initiation, progression and dissemination of cancer. Thus, signaling molecules are attractive targets for cancer therapeutics and enormous efforts have gone into the development of small molecule inhibitors of these pathways. However, regrettably, there has been only moderate progress to date, primarily in connection with the RAS signaling pathway. Oligonucleotide-based drugs potentially offer several advantages for addressing signaling pathways, including their exquisite selectivity and their ability to exploit both enzymatic and nonenzymatic targets. Nonetheless, there are problems inherent in the oligonucleotide approach, not the least being the challenge of effectively delivering these complex molecules to intracellular sites within tumors. This survey article will provide a selective review of recent studies where oligonucleotides were used to address cancer signaling and will discuss both positive aspects and limitations of those studies. This will be set in the context of an overview of various cancer signaling pathways and small molecule approaches to regulate those pathways. The survey will also evaluate the challenges and opportunities implicit in the oligonucleotide-based approach to cancer signaling and will point out several possibilities for future research.

scholarly journals Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1475
Author(s):  
Veronica Ruta ◽  
Vittoria Pagliarini ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Rna Processing ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Signal Transduction Pathways ◽  
Challenges And Opportunities ◽  
Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

scholarly journals Protein kinase Cδ inactivation inhibits cellular proliferation and decreases survival in human neuroendocrine tumors

2011 ◽  
Vol 18 (6) ◽  
pp. 759-771 ◽  
Author(s):  
Zhihong Chen ◽  
Lora W Forman ◽  
Kenneth A Miller ◽  
Brandon English ◽  
Asami Takashima ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Small Molecule ◽  
Cellular Proliferation ◽  
Small Molecule Inhibitors ◽  
Cancer Therapeutics ◽  
Therapeutic Modality ◽  
Ras Signaling ◽  
Normal Tissues ◽  
Induced Apoptosis

The concept of targeting cancer therapeutics toward specific mutations or abnormalities in tumor cells, which are not found in normal tissues, has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. Many human malignancies display activating mutations in the Ras family of signal-transducing genes or over-activity of p21Ras-signaling pathways. Carcinoid and other neuroendocrine tumors have been similarly demonstrated to have activation of Ras signaling directly by mutations in Ras, indirectly by loss of Ras-regulatory proteins, or via constitutive activation of upstream or downstream effector pathways of Ras, such as growth factor receptors or PI3-kinase and Raf/mitogen-activated protein kinases. We previously reported that aberrant activation of Ras signaling sensitizes cells to apoptosis when the activity of the PKCδ isozyme is suppressed and that PKCδ suppression is not toxic to cells with normal levels of p21Rassignaling. We demonstrate here that inhibition of PKCδ by a number of independent means, including genetic mechanisms (shRNA) or small-molecule inhibitors, is able to efficiently and selectively repress the growth of human neuroendocrine cell lines derived from bronchopulmonary, foregut, or hindgut tumors. PKCδ inhibition in these tumors also efficiently induced apoptosis. Exposure to small-molecule inhibitors of PKCδ over a period of 24 h is sufficient to significantly suppress cell growth and clonogenic capacity of these tumor cell lines. Neuroendocrine tumors are typically refractory to conventional therapeutic approaches. This Ras-targeted therapeutic approach, mediated through PKCδ suppression, which selectively takes advantage of the very oncogenic mutations that contribute to the malignancy of the tumor, may hold potential as a novel therapeutic modality.

Using Small Molecules To Identify Critical Signaling Pathways Of Mutant N-RAS In Acute Leukemia Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 169-169
Author(s):  
Atsushi Nonami ◽  
Martin Sattler ◽  
Ellen L. Weisberg ◽  
Jianming Zhang ◽  
Qingsong Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Ras Signaling ◽  
Over Expression ◽  
Simultaneous Inhibition ◽  
Chemical Screen ◽  
Multiple Signaling

Abstract Activating point mutations in NRAS are detected in more than 10% of AML patients, making NRAS an important therapeutic target. Using small molecules to directly target NRAS or inhibit post-translational modification, such as farnesylation, have been extensively investigated. The potential of strategies focused on targeting downstream effectors of RAS, such as RAF or MEK, has been limited by the complexity of RAS signaling, including redundancy and feedback loops. Large-scale RNAi screens have been used to identify genes (TBK1, STK33 and GATA2, for example) that are synthetically lethal with RAS mutations and these are being explored as therapeutic targets. Recognizing the complexity of RAS signaling, we tested the notion that small molecule screens designed to simultaneously inhibit multiple signaling pathways might identify combinations of pathways that are critical for NRAS signaling in leukemic cells. Initially, we created an experimental Ba/F3 cell line model that was completely dependent on oncogenic N-RAS-G12D for growth and survival. Knockdown of NRAS suppressed growth >95%, but could be rescued by interleukin-3 (IL-3). A chemical screen using panels of multi-targeted small molecule kinase inhibitors against BaF3-NRAS-G12D cells revealed a lead compound, NRAS1 (N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide), with high selectivity and sensitivity toward leukemia cell lines with NRAS mutations in vitro. A number of studies were then performed to investigate the targets of this compound. Transcriptional profiling before and after treatment of two AML cell lines with NRAS mutation (OCI-AML3 and KO52 cells, respectively) showed profiles similar to that obtained by knocking down NRAS, supporting the hypothesis that this compound suppressed NRAS signaling. Biochemical studies demonstrated that NRAS1 did not inhibit several classical targets of RAS signaling, including, RAF, MEK and ERK. In contrast, NRAS1 was found to substantially reduce AKT and RPS6 phosphorylation. Over-expression of a constitutively active allele of AKT, myrAKT, in Ba/F3-NRAS G12D cells conferred strong resistance to NRAS1, confirming that suppression of phospho-AKT may be important for the function of NRAS1. However, direct inhibition of AKT only partially recapitulated the effects of NRAS1. Kinase selectivity profiling of NRAS1 (1μM) in OCI-AML3 cells (EC50: 0.3μM) identified 13 major binding partners with more than 85% efficacy. The targets consisted mainly of SRC family proteins (ie SRC, FGR, and LYN) and MAPK family proteins (ie GCK, KSH, and p38), but not MEK1/2, ERK1/2 or AKT1-3. A series of analogs of NRAS1 was synthesized and structure/function studies were carried out. One compound, (LKB-0304601, 1% EC50 of original compound) lost the ability to bind to the MAP4K family of proteins, especially GCK (MAPK4K2). A combination effect was observed between a known GCK inhibitor, NG25, and a known allosteric AKT inhibitor, MK-2206, against mutant NRAS-expressing cells. This finding supports the hypothesis that simultaneous inhibition of GCK and AKT has suppressive activity against leukemia cells transformed by NRAS. Furthermore, a putative gate-keeper mutation introduced into GCK (GCK G96S) resulted in partial resistance to growth suppression by NG25 or NRAS1. Growth suppression of NRAS-transformed leukemic cells was further induced by knock-down of GCK by shRNAs in cells with mutant NRAS, THP-1 cells and MOLT-3, and this effect could be rescued by over-expression of GCK. Finally, in a xenotransplant model using NRAS-mutant-expressing OCI-AML3 cells and MOLT-3 cells, NRAS1 significantly reduced tumor burden and prolonged survival compared to controls. Overall, by using a chemical screen designed to inhibit multiple signaling pathways simultaneously in oncogene-addicted cells, followed by signaling studies, cell biological studies and kinase selectivity profiling, we found that simultaneous inhibition of AKT and GCK, by either NRAS1 or selective inhibitors, exhibits activity against NRAS-transformed leukemia cells. Disclosures: Griffin: Novartis Pharmaceuticals: Research Funding.

scholarly journals Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2308
Author(s):  
Jae Hyung Park ◽  
Woo Yang Pyun ◽  
Hyun Woo Park
Keyword(s):  
Signal Transduction ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Cancer Therapeutics ◽  
Building Blocks ◽  
Signal Transduction Pathways ◽  
Intermittent Fasting ◽  
Redox Potentials ◽  
Metabolic Phenotypes

Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs.

Synergistic Killing of Leukemic Cells by Small Molecule Inhibitors of the Pim Protein Kinases and Inactivators of Additional Signal Transduction Pathways.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 409-409
Author(s):  
Yingwei Lin ◽  
Zanna M Beharry ◽  
Elizabeth G Hill ◽  
Jin H. Song ◽  
Wenxue Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Cell Growth ◽  
Small Molecule ◽  
Single Agent ◽  
Signal Transduction Pathways ◽  
Pim Kinases ◽  
Cycle Arrest ◽  
Mtorc1 Pathway ◽  
P70 S6k

Abstract Abstract 409 The serine/threonine Pim kinases are up regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by c-Myc, N-Myc, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. Pim protein kinases were first identified as a proviral integration site in c-Myc overexpressor mice and function to greatly enhance lymphoma development. Here we demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases supplied by Vortex Biotechnology (Mt. Pleasant, SC), kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre T-LBL/T-ALL) being the most sensitive. Incubation of pre T-LBL cells with SMI-4a induced G1 phase cell cycle arrest secondary to a dose dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, inhibition of mTORC1 pathway based on decreases in phosphorylation of p70 S6K and 4E-BP1, two substrates of this enzyme, and down regulation of c-myc. We demonstrate that treatment with 60 mg/kg twice daily by oral gavage of SMI-4a inhibits subcutaneous growth of pre T-LBL tumors by an average of 47.9% (p< .05) in immuno-deficient animals without notable toxicity to weight, blood counts, cell morphology, or blood chemistries. To enhance the killing effect of SMI-4a we have examined a number of potential combination therapies. First, because we find in animals and cell culture that single agent SMI-4a treatment up regulates the ERK pathway and in the spleen and thymus of Pim1/2/3 knock out mice there is increased phosphorylation of ERK1/2, we combined SMI-4a and a MEK1/2 inhibitor, U0126 or PD184352. Our results demonstrate that this combination is highly synergistic in killing pre T-LBL cells in culture. Secondly, because SMI-4a shares a number of important properties with γ-secretase inhibitors (GSI), Notch1 pathway inhibitor, including inhibition of pre T-LBL cell growth, cell cycle arrest, induction of p27Kip1, mTORC1 inhibition, and c-Myc down regulation, we tested the possibility that these agents could be synergistic. We find that single agent treatment with SMI-4a at 5 μM or treatment with the GSI Z-IL-CHO at 10 μM kills less than 20% of pre T-LBL cells, whereas in combination these drugs kill 78% of these cells, suggesting a high degree of synergy. Finally, because SMI-4a inhibits the mTORC1 pathway decreasing the phosphorylation of two mTOR substrates, p70 S6K and 4E-BP1, and because Pim plays an essential role in the FLT3/ITD signaling pathway, we examined the activity of SMI-4a with or without rapamycin in myeloid leukemic MV4-11 carrying both MLL-AF4 and FLT3-ITD and the RS4-11 cell line containing only MLL-AF4. We find that these two agents are highly synergistic in culture. SMI-4a alone inhibited growth 18% and rapamycin 40% but when combined 76% of the cell growth was blocked. SMI-4a had no effect on RS 4-11 cells. Our results demonstrate that unique combinations of a potent Pim inhibitor, SMI-4a, and small molecule blockade of either the mTORC1, ERK or Notch pathways has promise as a novel combination strategies for the treatment of human leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways

2018 ◽  
Vol 4 (12) ◽  
pp. 1746-1754 ◽  
Author(s):  
Stella Hartmann ◽  
David J. Nusbaum ◽  
Kevin Kim ◽  
Saleem Alameh ◽  
Chi-Lee C. Ho ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Small Molecule ◽  
Signal Transduction Pathways

scholarly journals OS5.3 Quantitative signaling pathway analysis of Diffuse Intrinsic Pontine Glioma identifies two subtypes, respectively high TGFβ/MAPK-AP1 and high PI3K/HH pathway activity, which are potentially clinically actionable

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii11-iii11
Author(s):  
A van de Stolpe ◽  
W Verhaegh ◽  
L Holtzer
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Pi3k Pathway ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade Glioma ◽  
Signal Transduction Pathways ◽  
Low Grade ◽  
Pontine Glioma ◽  
Pathway Activity

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brain tumor (glioma), resistant to chemotherapy, with only a temporary response to radiotherapy and an extremely bad prognosis. Genomic abnormalities have been found, indicating abnormal activation of certain growth factor signaling pathways, while expression analysis suggests involvement of developmental signaling pathways.10–15 signal transduction pathways can drive cancer growth and metastasis. We have developed, and biologically validated, a method which enables quantitative measurements of functional activity of signal transduction pathways in individual cell/tissue samples, based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the transcription factor associated with the respective signalling pathway. A major envisioned clinical utility is prediction of therapy response. MATERIAL AND METHODS For signaling pathway analysis, Affymetrix expression microarray data were available (GEO dataset GSE26576) from 2 normal brain stem samples and from 6 low grade glioma and 26 DIPG samples (post-mortem after therapy). Of one DIPG patient samples were available before and after therapy. Signaling pathway activity scores were calculated for estrogen and androgen receptor, PI3K-FOXO, MAPK-AP1, JAK-STAT, NFκB, Hedgehog (HH), TGFβ, NOTCH and Wnt pathways. PI3K pathway activity is the reverse of FOXO activity, in the absence of oxidative stress (measured by SOD2 expression). Pathway activity scores were compared between normal tissue and low grade glioma samples and DIPG, and k-means cluster analysis was performed on the DIPG pathway activity scores. RESULTS After treatment, HH pathway activity was increased in DIPG compared to low grade glioma (p=0.0003), PI3K pathway activity scores showed large variations in activity in the DIPG group. Tumors with cell cycle (CDK4/6, CCND1-3) or Receptor Tyrosine Kinase-related gene amplifications had higher PI3K and HH pathway activity compared to tumors without identified amplifications (p<0.05) which, in contrast, had higher MAPK-AP1 pathway activity (p<0.002). Pathway-based clustering analysis revealed two DIPG clusters, C1: high TGFβ/MAPK-AP1 and low PI3K/HH pathway activity; C2: low TGFβ/MAPK-AP1, high PI3K/HH pathway activity. C1 best resembled low grade glioma. In the patient with pre/post treatment samples, a C1 pathway profile switched to a C2 profile after treatment. CONCLUSION Using our quantitative analysis of signaling pathway activity in post-treatment DIPG, two pathway activity subtypes were identified, of which the HH/PI3K high, TGFβ low activity subtype was associated with defined gene amplifications, and may have been induced by chemoradiation therapy. Clusters are supported by a clear biological rationale. Identified signaling pathways are potentially drug targetable.

scholarly journals MAPKs in development: insights from Dictyostelium signaling pathways

2011 ◽  
Vol 2 (1-2) ◽  
pp. 39-46 ◽  
Author(s):  
Jeffrey A. Hadwiger ◽  
Hoai-Nghia Nguyen
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Mapk Signaling ◽  
Signal Transduction Pathways ◽  
Signaling Specificity ◽  
Mitogen Activated Protein ◽  
Specific Proteins ◽  
Eukaryotic Organisms ◽  
External Signals ◽  
Multiple Signaling

AbstractMitogen activated protein kinases (MAPKs) play important roles in the development of eukaryotic organisms through the regulation of signal transduction pathways stimulated by external signals. MAPK signaling pathways have been associated with the regulation of cell growth, differentiation, and chemotaxis, indicating that MAPKs contribute to a diverse set of developmental processes. In most eukaryotes, the diversity of external signals is likely to far exceed the diversity of MAPKs, suggesting that multiple signaling pathways might share MAPKs. Do different signaling pathways converge before MAPK function or can MAPKs maintain signaling specificity through interactions with specific proteins? The genetic and biochemical analysis of MAPK pathways in simple eukaryotes such as Dictyostelium offers opportunities to investigate functional specificity of MAPKs in G-protein-mediated signal transduction pathways. This review considers the regulation and specificity of MAPK function in pathways that control Dictyostelium growth and development.

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