The unfolding role of ceramide in coordinating retinoid-based cancer therapy

2021 ◽  
Vol 478 (19) ◽  
pp. 3621-3642
Author(s):  
Botheina Ghandour ◽  
Ghassan Dbaibo ◽  
Nadine Darwiche
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressor ◽  
Therapeutic Interventions ◽  
Tumor Promoter ◽  
Cancer Development ◽  
Sphingolipid Metabolism ◽  
Retinoid Signaling ◽  
Combination Treatments ◽  
Ceramide Generation

Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a ‘tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer

scholarly journals Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

2016 ◽  
Vol 36 (9) ◽  
pp. 4381-4390 ◽  
Author(s):  
MARÍA JOSÉ GARCÍA CEBRIÁN ◽  
MONIKA BAUDEN ◽  
ROLAND ANDERSSON ◽  
STEFAN HOLDENRIEDER ◽  
DANIEL ANSARI
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Suppressor ◽  
Tumor Promoter ◽  
Cancer Tumor

scholarly journals Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy

2017 ◽  
Vol 243 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Lauren Y Maldonado ◽  
Diana Arsene ◽  
José M Mato ◽  
Shelly C Lu
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Human Cancer ◽  
Methionine Adenosyltransferase ◽  
Therapeutic Interventions ◽  
Cancer Development ◽  
Growth And Survival ◽  
Liver Cancers ◽  
Mat Genes

Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes – MAT1A, MAT2A, and MAT2B – with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes’ role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein–protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT’s tumorigenic role in identifying future targets for cancer therapy.

scholarly journals MicroRNAs Determining Carcinogenesis by Regulating Oncogenes and Tumor Suppressor Genes During Cell Cycle

MicroRNA ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 82-92 ◽  
Author(s):  
Fasoulakis Zacharias ◽  
Daskalakis George ◽  
Diakosavvas Michail ◽  
Papapanagiotou Ioannis ◽  
Theodora Marianna ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Cancer Development ◽  
Cell Cycle Regulators ◽  
Suppressor Genes ◽  
Cyclin Dependent Kinases ◽  
Multiple Cell ◽  
Therapeutic Tools

Aim:: To provide a review considering microRNAs regulating oncogenes and tumor suppressor genes during the different stages of cell cycle, controlling carcinogenesis. Methods:: The role of microRNAs involved as oncogenes’ and tumor suppressor genes’ regulators in cancer was searched in the relevant available literature in MEDLINE, including terms such as “microRNA”, “oncogenes”, “tumor suppressor genes”, “metastasis”, “cancer” and others. Results:: MicroRNAs determine the expression levels of multiple cell cycle regulators, such as cyclins, cyclin dependent kinases and other major cell cycle activators including retinoblastoma 1 (RB- 1) and p53, resulting in alteration and promotion/inhibition of the cell cycle. Conclusion:: MicroRNAs are proven to have a key role in cancer pathophysiology by altering the expression profile of different regulator proteins during cell division cycle and DNA replication. Thus, by acting as oncogenes and tumor suppressor genes, they can either promote or inhibit cancer development and formation, revealing their innovative role as biomarkers and therapeutic tools.

Abstract A28: Understanding the role of the tumor suppressor p53 in pancreatic cancer development

2018 ◽  
Author(s):  
Brittany M. Flowers ◽  
Patty B. Garcia ◽  
Barbara M. Grüner ◽  
Monte M. Winslow ◽  
Laura D. Attardi
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Suppressor ◽  
Cancer Development ◽  
Tumor Suppressor P53

scholarly journals The Hidden Role of Hydrogen Sulfide Metabolism in Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6562
Author(s):  
Rong-Hsuan Wang ◽  
Yu-Hsin Chu ◽  
Kai-Ti Lin
Keyword(s):  
Hydrogen Sulfide ◽  
Cancer Therapy ◽  
Cancer Progression ◽  
Cancer Development ◽  
Cancer Types ◽  
Cellular Bioenergetics ◽  
H2s Production ◽  
Anti Inflammation ◽  
Stimulation Of

Hydrogen Sulfide (H2S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H2S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H2S plays various roles during cancer development reveals opportunities to target H2S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H2S-mediated protein persulfidation and the detailed information about the dysregulation of H2S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H2S-mediated cancer progression and summarize current options to modulate H2S production for cancer therapy.

scholarly journals Apoptotic Sphingolipid Ceramide in Cancer Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Wei-Ching Huang ◽  
Chia-Ling Chen ◽  
Yee-Shin Lin ◽  
Chiou-Feng Lin
Keyword(s):  
Cell Death ◽  
Heat Stress ◽  
Cancer Therapy ◽  
Therapy Resistance ◽  
Sphingolipid Metabolism ◽  
Apoptotic Signaling ◽  
Chemical Agents ◽  
Cancer Cell Survival ◽  
Extracellular Stimuli ◽  
Ceramide Generation

Apoptosis, also called programmed cell death, is physiologically and pathologically involved in cellular homeostasis. Escape of apoptotic signaling is a critical strategy commonly used for cancer tumorigenesis. Ceramide, a derivative of sphingolipid breakdown products, acts as second messenger for multiple extracellular stimuli including growth factors, chemical agents, and environmental stresses, such as hypoxia, and heat stress as well as irradiation. Also, ceramide acts as tumor-suppressor lipid because a variety of stress stimuli cause apoptosis by increasing intracellular ceramide to initiate apoptotic signaling. Defects on ceramide generation and sphingolipid metabolism are developed for cancer cell survival and cancer therapy resistance. Alternatively, targeting ceramide metabolism to correct these defects might provide opportunities to overcome cancer therapy resistance.

Role of Tumor Suppressor Protein p53 in Apoptosis and Cancer Therapy

2011 ◽  
Vol 03 (06) ◽  
Author(s):  
Naga Deepthi CH ◽  
VVL Pavan Kumar ◽  
Ramesh babu ◽  
U Indirapriya darshini
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressor ◽  
Tumor Suppressor Protein ◽  
Tumor Suppressor Protein P53 ◽  
Protein P53

scholarly journals Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Fatemeh Aliabadi ◽  
Beheshteh Sohrabi ◽  
Ebrahim Mostafavi ◽  
Hamidreza Pazoki-Toroudi ◽  
Thomas J. Webster
Keyword(s):  
Cancer Therapy ◽  
Ubiquitin Proteasome System ◽  
Tumour Suppressor ◽  
The Other ◽  
Cancer Development ◽  
Chemotherapy Drugs ◽  
Advantages And Disadvantages ◽  
Fundamental Understanding ◽  
Ubiquitin Proteasome

Despite all the other cells that have the potential to prevent cancer development and metastasis through tumour suppressor proteins, cancer cells can upregulate the ubiquitin–proteasome system (UPS) by which they can degrade tumour suppressor proteins and avoid apoptosis. This system plays an extensive role in cell regulation organized in two steps. Each step has an important role in controlling cancer. This demonstrates the importance of understanding UPS inhibitors and improving these inhibitors to foster a new hope in cancer therapy. UPS inhibitors, as less invasive chemotherapy drugs, are increasingly used to alleviate symptoms of various cancers in malignant states. Despite their success in reducing the development of cancer with the lowest side effects, thus far, an appropriate inhibitor that can effectively inactivate this system with the least drug resistance has not yet been fully investigated. A fundamental understanding of the system is necessary to fully elucidate its role in causing/controlling cancer. In this review, we first comprehensively investigate this system, and then each step containing ubiquitination and protein degradation as well as their inhibitors are discussed. Ultimately, its advantages and disadvantages and some perspectives for improving the efficiency of these inhibitors are discussed.

Sign in / Sign up

Export Citation Format

Share Document