The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

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Acid ceramidase, a double-edged sword in cancer aggression: A minireview

Current Cancer Drug Targets ◽

10.2174/1568009620666201223154621 ◽

2020 ◽

Vol 20 ◽

Author(s):

Helen Shiphrah Vethakanraj ◽

Niveditha Chandrasekaran ◽

Ashok Kumar Sekar

Keyword(s):

Cell Fate ◽

Cancer Progression ◽

Potential Role ◽

Tumour Progression ◽

Acid Ceramidase ◽

The Core ◽

The Past ◽

Sphingosine 1 Phosphate ◽

Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

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Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Molecular and Cellular Biology ◽

10.1128/mcb.00266-15 ◽

2015 ◽

Vol 35 (16) ◽

pp. 2716-2728 ◽

Cited By ~ 57

Author(s):

Lluis Morey ◽

Alexandra Santanach ◽

Luciano Di Croce

Keyword(s):

Cell Fate ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Basic Research ◽

Cell Types ◽

Pluripotency Factors ◽

Perfect System

Embryonic stem cells (ESCs) are characterized by their ability to self-renew and to differentiate into all cell types of a given organism. Understanding the molecular mechanisms that govern the ESC state is of great interest not only for basic research—for instance, ESCs represent a perfect system to study cellular differentiationin vitro—but also for their potential implications in human health, as these mechanisms are likewise involved in cancer progression and could be exploited in regenerative medicine. In this minireview, we focus on the latest insights into the molecular mechanisms mediated by the pluripotency factors as well as their roles during differentiation. We also discuss recent advances in understanding the function of the epigenetic regulators, Polycomb and MLL complexes, in ESC biology.

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Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

BioMed Research International ◽

10.1155/2015/161508 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 28

Author(s):

Sabrina Bimonte ◽

Antonio Barbieri ◽

Domenica Rea ◽

Giuseppe Palma ◽

Antonio Luciano ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Mouse Model ◽

Cancer Progression ◽

Breast Cancer Progression ◽

Cancer Cell Growth ◽

Patients With Cancer ◽

Human Breast Carcinoma Cells

Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Severalin vitroandin vivostudies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performedin vitrostudies on ER-negative human breast carcinoma cells, MDA.MB231 andin vivostudies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphinein vitroenhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells.In vivostudies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

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Multifaced roles of PLAC8 in cancer

Biomarker Research ◽

10.1186/s40364-021-00329-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Misha Mao ◽

Yifan Cheng ◽

Jingjing Yang ◽

Yongxia Chen ◽

Ling Xu ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Molecular Function ◽

Cancer Cell Growth ◽

The Impact ◽

Functional Output

AbstractThe role of PLAC8 in tumorigenesis has been gradually elucidated with the development of research. Although there are common molecular mechanisms that enforce cell growth, the impact of PLAC8 is varied and can, in some instances, have opposite effects on tumorigenesis. To systematically understand the role of PLAC8 in tumors, the molecular functions of PLAC8 in cancer will be discussed by focusing on how PLAC8 impacts tumorigenesis when it arises within tumor cells and how these roles can change in different stages of cancer progression with the ultimate goal of suppressing PLAC8-relevant cancer behavior and related pathologies. In addition, we highlight the diversity of PLAC8 in different tumors and its functional output beyond cancer cell growth. The comprehension of PLAC8’s molecular function might provide new target and lead to the development of novel anticancer therapies.

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Roles of sphingosine-1-phosphate signaling in cancer

Cancer Cell International ◽

10.1186/s12935-019-1014-8 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 13

Author(s):

Peng Wang ◽

Yonghui Yuan ◽

Wenda Lin ◽

Hongshan Zhong ◽

Ke Xu ◽

...

Keyword(s):

Cell Fate ◽

Cancer Progression ◽

Therapeutic Potential ◽

Receptor Activation ◽

Signaling Cascades ◽

Lipid Mediator ◽

Downstream Signaling ◽

Sphingosine 1 Phosphate ◽

Sphingosine Kinases ◽

And Migration

AbstractThe potent pleiotropic lipid mediator sphingosine-1-phosphate (S1P) participates in numerous cellular processes, including angiogenesis and cell survival, proliferation, and migration. It is formed by one of two sphingosine kinases (SphKs), SphK1 and SphK2. These enzymes largely exert their various biological and pathophysiological actions through one of five G protein-coupled receptors (S1PR1–5), with receptor activation setting in motion various signaling cascades. Considerable evidence has been accumulated on S1P signaling and its pathogenic roles in diseases, as well as on novel modulators of S1P signaling, such as SphK inhibitors and S1P agonists and antagonists. S1P and ceramide, composed of sphingosine and a fatty acid, are reciprocal cell fate regulators, and S1P signaling plays essential roles in several diseases, including inflammation, cancer, and autoimmune disorders. Thus, targeting of S1P signaling may be one way to block the pathogenesis and may be a therapeutic target in these conditions. Increasingly strong evidence indicates a role for the S1P signaling pathway in the progression of cancer and its effects. In the present review, we discuss recent progress in our understanding of S1P and its related proteins in cancer progression. Also described is the therapeutic potential of S1P receptors and their downstream signaling cascades as targets for cancer treatment.

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Ribosome Biogenesis Alterations in Colorectal Cancer

Cells ◽

10.3390/cells9112361 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2361

Author(s):

Sophie Nait Slimane ◽

Virginie Marcel ◽

Tanguy Fenouil ◽

Frédéric Catez ◽

Jean-Christophe Saurin ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Synthesis ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Progression ◽

Ribosome Biogenesis ◽

Predictive Biomarkers ◽

Cancer Cell Growth ◽

Therapeutic Drugs ◽

Key Driver

Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.

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Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process

Cancers ◽

10.3390/cancers12102896 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2896

Author(s):

Naofumi Mukaida ◽

Di Zhang ◽

So-ichiro Sasaki

Keyword(s):

Bone Marrow ◽

Bone Metastasis ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Associated Fibroblasts ◽

Cancer Cell Growth ◽

Lung Cancers ◽

Osteoclast Activation

Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients’ quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.

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