scholarly journals PI3K Functions in Cancer Progression, Anticancer Immunity and Immune Evasion by Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Francesco Dituri ◽  
Antonio Mazzocca ◽  
Gianluigi Giannelli ◽  
Salvatore Antonaci
Keyword(s):  
Immune Responses ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Pi3k Pathway ◽  
Point Of View ◽  
Phosphatidylinositol 3 Kinase ◽  
Pharmacological Agents ◽  
Cellular Processes ◽  
Immunological Surveillance ◽  
Potential Benefits

The immunological surveillance of tumors relies on a specific recognition of cancer cells and their associate antigens by leucocytes of innate and adaptive immune responses. However, a dysregulated cytokine release can lead to, or be associated with, a failure in cell-cell recognition, thus, allowing cancer cells to evade the killing system. The phosphatidylinositol 3-kinase (PI3K) pathway regulates multiple cellular processes which underlie immune responses against pathogens or malignant cells. Conversely, there is accumulating evidence that the PI3K pathway is involved in the development of several malignant traits of cancer cells as well as their escape from immunity. Herein, we review the counteracting roles of PI3K not only in antitumor immune response but also in the mechanisms that cancer cells use to avoid leukocyte attack. In addition, we discuss, from antitumor immunological point of view, the potential benefits and disadvantages arising from use of anticancer pharmacological agents targeting the PI3K pathway.

TREX1 is a checkpoint for innate immune sensing of DNA damage that fosters cancer immune resistance

2017 ◽  
Vol 1 (5) ◽  
pp. 509-515
Author(s):  
Sandra Demaria ◽  
Claire Vanpouille-Box
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Cancer Progression ◽  
Type I ◽  
Replicative Stress ◽  
Immune Resistance ◽  
Cytoplasmic Dna ◽  
Autoimmune Pathology

Genomic instability is a hallmark of neoplastic transformation that leads to the accumulation of mutations, and generates a state of replicative stress in neoplastic cells associated with dysregulated DNA damage repair (DDR) responses. The importance of increasing mutations in driving cancer progression is well established, whereas relatively little attention has been devoted to the DNA displaced to the cytosol of cancer cells, a byproduct of genomic instability and of the ensuing DDR response. The presence of DNA in the cytosol promotes the activation of viral defense pathways in all cells, leading to activation of innate and adaptive immune responses. In fact, the improper accumulation of cytosolic DNA in normal cells is known to drive severe autoimmune pathology. Thus, cancer cells must evade cytoplasmic DNA detection pathways to avoid immune-mediated destruction. The main sensor for cytoplasmic DNA is the cyclic GMP–AMP synthase, cGAS. Upon activation by cytosolic DNA, cGAS catalyzes the formation of the second messenger cGAMP, which activates STING (stimulator of IFN genes), leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated antiviral and antitumor immunity, and its production by cancer cells can be subverted by several mechanisms. However, the key upstream regulator of cytosolic DNA-mediated immune stimulation is the DNA exonuclease 3′-repair exonuclease 1 (TREX1). Here, we will discuss evidence in support of a role of TREX1 as an immune checkpoint that, when up-regulated, hinders the development of antitumor immune responses.

scholarly journals Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells

2008 ◽  
Vol 29 (2) ◽  
pp. 559-569 ◽  
Author(s):  
Vladimir L. Gabai ◽  
Julia A. Yaglom ◽  
Todd Waldman ◽  
Michael Y. Sherman
Keyword(s):  
Heat Shock ◽  
Epithelial Cells ◽  
Heat Shock Protein ◽  
Cancer Cells ◽  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
P53 Pathway ◽  
Extracellular Signal ◽  
Kinase Cascade ◽  
Dependent Pathway

ABSTRACT The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells, but not in untransformed breast epithelial cells, triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of phosphatidylinositol 3-kinase (PI3K). Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with the Ras oncogene. In this pathway, extracellular signal-regulated kinases (ERKs) were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become “addicted” to this heat shock protein.

scholarly journals Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 238 ◽  
Author(s):  
Mei Shan Ong ◽  
Shuo Deng ◽  
Clarissa Esmeralda Halim ◽  
Wanpei Cai ◽  
Tuan Zea Tan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cytoskeletal Proteins ◽  
Cellular Processes ◽  
Oxidative Stresses ◽  
Cytoskeletal Responses ◽  
Therapeutic Perspective ◽  
Promote Tumour Development ◽  
Oncogenic Signalling

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression.

scholarly journals NFKB1 and Cancer: Friend or Foe?

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 133 ◽  
Author(s):  
Julia Concetti ◽  
Caroline L Wilson
Keyword(s):  
Immune Responses ◽  
Cancer Progression ◽  
Multiple Roles ◽  
Current Evidence ◽  
Cellular Processes ◽  
Specific Manner ◽  
Organ Specific ◽  
A Cell ◽  
Potential Cancer

Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, it is not surprising that dysregulated and chronic NF-κB signalling can have a profound impact on cellular homeostasis. Here we discuss NFKB1 (p105/p50), one of the five subunits of NF-κB, widely implicated in carcinogenesis, in some cases driving cancer progression and in others acting as a tumour-suppressor. The complexity of the role of this subunit lies in the multiple dimeric combination possibilities as well as the different interacting co-factors, which dictate whether gene transcription is activated or repressed, in a cell and organ-specific manner. This review highlights the multiple roles of NFKB1 in the development and progression of different cancers, and the considerations to make when attempting to manipulate NF-κB as a potential cancer therapy.

Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils

2018 ◽  
Vol 18 (1) ◽  
pp. 87-109 ◽  
Author(s):  
Manobjyoti Bordoloi ◽  
Surovi Saikia ◽  
Bhaskor Kolita ◽  
Rajeev Sarmah ◽  
Sonali Roy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Essential Oil ◽  
Essential Oils ◽  
Cancer Cells ◽  
Pi3k Pathway ◽  
Lung Cancer Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Anti Cancer ◽  
A549 Lung ◽  
Phosphatidylinositol 3

Background: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents. Materials and Methods: The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells. Results: The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway. Conclusion: Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.

scholarly journals Class IA PI3K regulatory subunits: p110-independent roles and structures

2020 ◽  
Vol 48 (4) ◽  
pp. 1397-1417
Author(s):  
Millie Fox ◽  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
Current Knowledge ◽  
Pi3k Pathway ◽  
Protein Domain ◽  
Phosphatidylinositol 3 Kinase ◽  
Catalytic Subunits ◽  
Regulatory Subunits ◽  
Cellular Processes ◽  
Additional Control ◽  
Domain Interactions

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of many cellular processes including cell survival, growth, proliferation and motility. Not surprisingly therefore, the PI3K pathway is one of the most frequently mutated pathways in human cancers. In addition to their canonical role as part of the PI3K holoenzyme, the class IA PI3K regulatory subunits undertake critical functions independent of PI3K. The PI3K regulatory subunits exist in excess over the p110 catalytic subunits and therefore free in the cell. p110-independent p85 is unstable and exists in a monomer-dimer equilibrium. Two conformations of dimeric p85 have been reported that are mediated by N-terminal and C-terminal protein domain interactions, respectively. The role of p110-independent p85 is under investigation and it has been found to perform critical adaptor functions, sequestering or influencing compartmentalisation of key signalling proteins. Free p85 has roles in glucose homeostasis, cellular stress pathways, receptor trafficking and cell migration. As a regulator of fundamental pathways, the amount of p110-independent p85 in the cell is critical. Factors that influence the monomer-dimer equilibrium of p110-independent p85 offer additional control over this system, disruption to which likely results in disease. Here we review the current knowledge of the structure and functions of p110-independent class IA PI3K regulatory subunits.

scholarly journals Oncometabolites and the response to radiotherapy

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Kexu Xiang ◽  
Verena Jendrossek ◽  
Johann Matschke
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Multidisciplinary Treatment ◽  
Metabolic Enzymes ◽  
Therapeutic Effects ◽  
Dna Double Strand Breaks ◽  
Cellular Processes ◽  
Epigenetic Modulation

AbstractRadiotherapy (RT) is applied in 45–60% of all cancer patients either alone or in multimodal therapy concepts comprising surgery, RT and chemotherapy. However, despite technical innovations approximately only 50% are cured, highlight a high medical need for innovation in RT practice. RT is a multidisciplinary treatment involving medicine and physics, but has always been successful in integrating emerging novel concepts from cancer and radiation biology for improving therapy outcome. Currently, substantial improvements are expected from integration of precision medicine approaches into RT concepts.Altered metabolism is an important feature of cancer cells and a driving force for malignant progression. Proper metabolic processes are essential to maintain and drive all energy-demanding cellular processes, e.g. repair of DNA double-strand breaks (DSBs). Consequently, metabolic bottlenecks might allow therapeutic intervention in cancer patients.Increasing evidence now indicates that oncogenic activation of metabolic enzymes, oncogenic activities of mutated metabolic enzymes, or adverse conditions in the tumor microenvironment can result in abnormal production of metabolites promoting cancer progression, e.g. 2-hyroxyglutarate (2-HG), succinate and fumarate, respectively. Interestingly, these so-called “oncometabolites” not only modulate cell signaling but also impact the response of cancer cells to chemotherapy and RT, presumably by epigenetic modulation of DNA repair.Here we aimed to introduce the biological basis of oncometabolite production and of their actions on epigenetic regulation of DNA repair. Furthermore, the review will highlight innovative therapeutic opportunities arising from the interaction of oncometabolites with DNA repair regulation for specifically enhancing the therapeutic effects of genotoxic treatments including RT in cancer patients.

scholarly journals Molecular target: pan-AKT in gastric cancer

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000728 ◽  
Author(s):  
Byung Woog Kang ◽  
Ian Chau
Keyword(s):  
Gastric Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Activation ◽  
Cellular Processes ◽  
Downstream Effectors ◽  
Downstream Effects ◽  
Attractive Therapeutic Target ◽  
Mtor Signalling

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.

Sign in / Sign up

Export Citation Format

Share Document