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Yang X, Chen J, Wang Y, Wu Y, Zhang J. Managing Irinotecan-Induced Diarrhea: A Comprehensive Review of Therapeutic Interventions in Cancer Treatment. Pharmaceuticals (Basel) 2025; 18:359. [PMID: 40143136 PMCID: PMC11944746 DOI: 10.3390/ph18030359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) is often severe, leading to hospitalization, dosage adjustments, and in some cases, treatment discontinuation, which can significantly impact therapeutic outcomes. A multitude of pharmacological agents have been investigated in preclinical and clinical studies with the aim of reducing or preventing the onset of delayed diarrhea associated with CPT-11. This comprehensive review examines the underlying mechanisms of CPT-11-triggered delayed diarrhea and discusses the experimental medications and strategies that have been utilized to combat this adverse effect. This review encompasses an exploration of chemical formulations, the application of traditional Chinese medicine, and the advent of innovative drug delivery systems. It is anticipated that this article will serve as a valuable resource for both novice researchers in the realm of irinotecan chemotherapy and for those who are well-versed in the field, including experts and practicing clinicians.
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Affiliation(s)
- Xiaoqin Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (X.Y.); (J.C.)
| | - Jiamei Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (X.Y.); (J.C.)
| | - Yitao Wang
- State Key Laboratory of Quality Research in Traditional Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China;
| | - Yihan Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (X.Y.); (J.C.)
| | - Jinming Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (X.Y.); (J.C.)
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Voutsadakis IA. Treatment of extended RAS/ BRAF wild-type metastatic colorectal cancer with anti-EGFR antibody combinations. Pharmacogenomics 2025; 26:39-52. [PMID: 40097366 PMCID: PMC11988258 DOI: 10.1080/14622416.2025.2479414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/11/2025] [Indexed: 03/19/2025] Open
Abstract
Receptor tyrosine kinase pathways are frequently deregulated in cancer. Inhibiting these pathways with small molecule inhibitors or monoclonal antibodies has become a crucial addition to the therapeutic armamentarium in oncology. Since the introduction of drugs that target receptor tyrosine kinase pathways, it has become evident that not all patients respond to treatment. Therefore, biomarkers to predict response and benefit of drugs targeting tyrosine kinases have been sought. Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), one of the four receptors of the EGFR family were among the first targeted therapies used in solid tumors. Two drugs of this class, cetuximab and panitumumab, have been used in patients with metastatic colorectal cancer initially without any biomarker requirement. Soon, it became clear that responses were mostly observed in patients without mutations in KRAS oncogene. Currently, additional mutations of the pathway, including non-exon 2 mutations in KRAS, mutations in the homologous GTPase NRAS, in kinase BRAF and PIK3CA and other pathway proteins, have been added in the evaluation for responsiveness prediction to cetuximab and panitumumab. In this review, the predictive biomarker landscape for anti-EGFR monoclonal antibody inhibitors in metastatic colorectal cancers with no extended RAS and BRAF mutations will be examined.
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Affiliation(s)
- Ioannis A. Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON, Canada
- Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada
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Cavalu S, Saber S, Ramadan A, Elmorsy EA, Hamad RS, Abdel-Reheim MA, Youssef ME. Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders. FASEB J 2024; 38:e70030. [PMID: 39221499 DOI: 10.1096/fj.202400823r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/07/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.
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Affiliation(s)
- Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Asmaa Ramadan
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Elsayed A Elmorsy
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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Voutsadakis IA. PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes. Cancer Genomics Proteomics 2024; 21:533-548. [PMID: 39191495 PMCID: PMC11363921 DOI: 10.21873/cgp.20470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND/AIM Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations. MATERIALS AND METHODS The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA. RESULTS PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable. CONCLUSION Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON, Canada;
- Division of Clinical Sciences, Section of Internal Medicine, Northern Ontario School of Medicine, Sudbury, ON, Canada
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Voutsadakis IA. High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology. Cancer Treat Res Commun 2023; 36:100746. [PMID: 37494750 DOI: 10.1016/j.ctarc.2023.100746] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/16/2023] [Accepted: 07/20/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Colorectal cancers with defects in the Mismatch Repair (MMR) system represent a minority of the disease. MMR defective cancers are characterized by high Tumor Mutation Burden (TMB) and are sensitive to immunotherapy with immune checkpoint inhibitors. In contrast, the majority of colorectal cancers are MMR proficient (Microsatellite Stable, MSS) and display a low TMB. However, a few of these MSS cancers have high TMB. METHODS Published genomic studies of colorectal cancers were examined to identify cases profiled as MSS and having a TMB above 10 mutations / Mb. Data from four studies detailed in the cBioportal for cancer genomics site and providing data on MSI status were examined. RESULTS In the MSK study of metastatic colorectal cancers, 7.5% of patients with MSS tumors had a high TMB of more than 10 mutations/ Mb. The MSK study of localized rectal cancers showed that 9.5% of patients with MSS tumors had a high TMB. The DFCI cohort included 10 patients with TMB above 10 mutations/ Mb characterized as MSS and not having MMR or proofreading polymerases mutations. Mutations in genes encoding for proteins of the KRAS pathways were more frequent in MSS tumors with high TMB than in counterparts with low TMB. Moreover, genes involved in DNA damage response and in epigenetic regulations were more frequently mutated in MSS colorectal cancers with high TMB. CONCLUSION Alterations of the KRAS signal transduction pathways, DDR gene mutations and epigenetic modifier mutations may contribute to increase mutation burden in subsets of MSS colorectal cancers.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, Ontario, P6B 0A8, Canada; Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Voutsadakis IA. KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics. Crit Rev Oncol Hematol 2023; 186:103987. [PMID: 37059275 DOI: 10.1016/j.critrevonc.2023.103987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/13/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the most prevalent malignancies and its molecular pathogenesis has been intensely investigated for several decades. As a result, great progress has been made and targeted therapies have been introduced in the clinic. This paper examines colorectal cancers based on two of the most common molecular alterations, KRAS and PIK3CA mutations as a basis for therapeutic targeting. METHODS Two publicly available genomic series with clinical data were evaluated for prevalence and characteristics of cases with and without KRAS and PIK3CA mutations and the literature was reviewed for relevant information on the therapeutic implication of these alterations as well as other coincident alterations to derive therapeutic individualized options of targeted treatments. RESULTS Colorectal cancers without KRAS and PIK3CA mutations represent the most prevalent group (48% to 58% of patients) and present therapeutic targeted opportunities with BRAF inhibitors and immune checkpoint inhibitors in the subsets with BRAF mutations (15% to 22%) and Microsatellite Instability (MSI, 14% to 16%), respectively. The second most prevalent sub-set, with KRAS mutations and PIK3CA wild type, representing 20% to 25% of patients, has currently few targeted options, besides specific KRAS G12C inhibitors for the small percentage of cases (9%-10%) that bear this mutation. Cancers with KRAS wild type and PIK3CA mutations are observed in 12% to 14% of colorectal cancer patients, harbor the highest percentage of cases with BRAF mutations and Microsatellite Instability (MSI), and are candidates for the respective targeted therapies. New targeted therapies in development, such as ATR inhibitors could be effective in cases with ATM mutations and ARID1A mutations that are also most prevalent in this sub-group (14% to 22% and 30%, respectively). KRAS and PIK3CA double mutant cancers have also few targeted options currently and could benefit from combination therapies with PI3K inhibitors and new KRAS inhibitors in development. CONCLUSION The backbone of common KRAS and PIK3CA mutations is a rational frame for development of therapeutic algorithms in colorectal cancer and can help guide new drug therapies development. In addition, the prevalence of different molecular groups presented here may help with planning of combination clinical trials by providing estimations of sub-sets with more than one alteration.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada, and Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Voutsadakis IA. The Genomic Environment of BRAF Mutated and BRAF/PIK3CA Double Mutated Colorectal Cancers. J Clin Med 2022; 11:jcm11175132. [PMID: 36079062 PMCID: PMC9456575 DOI: 10.3390/jcm11175132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Colorectal cancer represents the most prevalent gastrointestinal malignancy. Prognosis of metastatic disease has improved in recent years with the introduction of effective systemic therapies, but mean survival remains in the range of two to three years. Targeted therapies based on specific molecular alterations in sub-sets of colorectal cancers have the potential of contributing to therapeutic progress. BRAF and PIK3CA are oncogenic kinases commonly mutated in colorectal cancers and can be targeted through small molecule kinase inhibitors. Methods: Clinical and genomic data from two extensive series of colorectal cancers were interrogated to define the molecular characteristics of cancers with BRAF mutations with and without concomitant mutations in PIK3CA. Results: Colorectal cancers that are BRAF and PIK3CA double mutants represent a small minority of about 5% of colorectal cancers in the two examined series of mostly localized disease. They also represent about one third of all BRAF mutated colorectal cancers. Most mutations in BRAF are classic V600E mutations. A high prevalence of MSI and CIMP is observed in BRAF mutated colorectal cancers with or without PIK3CA mutations. Mutations in tumor suppressors FBXW7 and ATM display a higher prevalence in BRAF mutated cancers. The prognosis of BRAF mutated colorectal cancers with or without PIK3CA mutations is not significantly different than counterparts with wild type BRAF. This contrasts with the known adverse prognostic effect of BRAF in metastatic disease and relates to the different prevalence of MSI in mutant BRAF localized versus metastatic colorectal cancers. Conclusions: BRAF mutations are the defining molecular alterations in double mutant BRAF and PIK3CA colorectal cancers as determined by increased MSI and CIMP in BRAF subsets with and without PIK3CA mutations. Moreover, BRAF mutated cancers with and without PIK3CA mutations are characterized by the absence of KRAS mutations and a lower prevalence of APC mutations than BRAF wild type counterparts. Mismatch-repair-associated gene mutations display higher frequencies in BRAF mutated colorectal cancers. Despite the absence of prognosis implications of BRAF mutations in the studied cohorts of mostly localized cancers, such mutations could be prognostic in certain subsets. The presence of mutations in other genes, such as ATM and high MSI status present opportunities for combination therapies.
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Affiliation(s)
- Ioannis A. Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON P6B 0A8, Canada; or
- Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON P6B 0A8, Canada
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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Biomarkers of Trifluridine-Tipiracil Efficacy. J Clin Med 2021; 10:jcm10235568. [PMID: 34884270 PMCID: PMC8658167 DOI: 10.3390/jcm10235568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 11/17/2022] Open
Abstract
Trifluridine/tipiracil (TAS-102) is a newer generation chemotherapy that has been approved for the later-line treatment of metastatic colorectal and gastric/gastroesophageal adenocarcinomas. The oral drug provides a modest benefit of prolongation of survival over placebo in pretreated patients with these cancers with acceptable toxicity. Studies have shown rare objective responses (2-4%), and the disease control rates were 44% in both colorectal and gastric cancer randomized trials. Thus, the majority of patients progress through treatment and are burdened by toxicities. To better characterize the sub-group of patients with a higher probability of benefit from trifluridine/tipiracil, predictive biomarkers have been sought using data from randomized trials as well as from non-randomized trials and real-world series. Biomarkers examined include clinical characteristics of the patients, laboratory tests, and tumor derived biomarkers. These studies show that early neutropenia on treatment, and ratios of leukocyte subsets, are potential biomarkers able to predict trifluridine/tipiracil benefit. Combinations of laboratory values and clinical characteristics and proteins involved in trifluridine transport and activation have been examined with initial positive results.
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Rubio AJ, Bencomo-Alvarez AE, Young JE, Velazquez VV, Lara JJ, Gonzalez MA, Eiring AM. 26S Proteasome Non-ATPase Regulatory Subunits 1 (PSMD1) and 3 (PSMD3) as Putative Targets for Cancer Prognosis and Therapy. Cells 2021; 10:2390. [PMID: 34572038 PMCID: PMC8472613 DOI: 10.3390/cells10092390] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/30/2022] Open
Abstract
Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a result, the anti-cancer drugs bortezomib, carfilzomib, and ixazomib targeting the 26S proteasome were developed to treat multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, among others. Despite success, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options. We recently demonstrated that knockdown of the 19S regulatory components, 26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3), resulted in increased apoptosis of chronic myeloid leukemia (CML) cells, but had no effect on normal controls, suggesting they may be good targets for therapy. Therefore, we hypothesized that PSMD1 and PSMD3 are potential targets for anti-cancer therapeutics and that their relevance stretches beyond CML to other types of cancers. In the present study, we analyzed PSMD1 and PSMD3 mRNA and protein expression in cancerous tissue versus normal controls using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), comparing expression with overall survival. Altogether, our data suggest that PSMD1 and PSMD3 may be novel putative targets for cancer prognosis and therapy that are worthy of future investigation.
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Affiliation(s)
- Andres J Rubio
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - Alfonso E Bencomo-Alvarez
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - James E Young
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - Vanessa V Velazquez
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - Joshua J Lara
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - Mayra A Gonzalez
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
| | - Anna M Eiring
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
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Voutsadakis IA. Mutations of p53 associated with pancreatic cancer and therapeutic implications. Ann Hepatobiliary Pancreat Surg 2021; 25:315-327. [PMID: 34402431 PMCID: PMC8382872 DOI: 10.14701/ahbps.2021.25.3.315] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/19/2021] [Accepted: 05/31/2021] [Indexed: 12/30/2022] Open
Abstract
Pancreatic adenocarcinoma is a malignancy with rising incidence and grim prognosis. Despite improvements in therapeutics for treating metastatic pancreatic cancer, this disease is invariably fatal with survival time less than a few years. New molecular understanding of the pathogenesis of pancreatic adenocarcinoma based on efforts led by The Cancer Genome Atlas and other groups has elucidated the landscape of this disease and started to produce therapeutic results, leading to the first introduction of targeted therapies for subsets of pancreatic cancers bearing specific molecular lesions such as BRCA mutations. These efforts have highlighted that subsets of pancreatic cancers are particularly sensitive to chemotherapy. The most common molecular lesions in pancreatic adenocarcinomas are mutations in an oncogene KRAS and the TP53 gene that encodes for tumor suppressor protein p53. This paper will review the landscape of pancreatic cancers, focusing on mutations of p53, a major tumor suppressor protein, in pancreatic cancers and possible therapeutic repercussions.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON, Canada.,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada
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Gómez de Segura I, Ahechu P, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Becerril S, Unamuno X, Mentxaka A, Baixauli J, Valentí V, Moncada R, Silva C, Frühbeck G, Catalán V. Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling. Int J Mol Sci 2021; 22:ijms22168485. [PMID: 34445187 PMCID: PMC8395192 DOI: 10.3390/ijms22168485] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). METHODS Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. RESULTS Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
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Affiliation(s)
- Iranzu Gómez de Segura
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
| | - Patricia Ahechu
- Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (P.A.); (J.B.); (V.V.)
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
| | - Xabier Unamuno
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
| | - Amaia Mentxaka
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
| | - Jorge Baixauli
- Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (P.A.); (J.B.); (V.V.)
| | - Víctor Valentí
- Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (P.A.); (J.B.); (V.V.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
| | - Rafael Moncada
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Department of Anesthesia, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Camilo Silva
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Correspondence: (G.F.); (V.C.); Tel.: +34-9-4825-5400 (ext. 4484) (G.F.); +34-9-4825-5400 (ext. 5133) (V.C.)
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (I.G.d.S.); (J.G.-A.); (A.R.); (B.R.); (S.B.); (X.U.); (A.M.)
- CIBEROBN, Instituto de Salud Carlos III, 31008 Pamplona, Spain; (R.M.); (C.S.)
- Obesity and Adipobiology Group, IdiSNA, 31008 Pamplona, Spain
- Correspondence: (G.F.); (V.C.); Tel.: +34-9-4825-5400 (ext. 4484) (G.F.); +34-9-4825-5400 (ext. 5133) (V.C.)
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3q26 Amplifications in Cervical Squamous Carcinomas. ACTA ACUST UNITED AC 2021; 28:2868-2880. [PMID: 34436017 PMCID: PMC8395483 DOI: 10.3390/curroncol28040251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/17/2021] [Accepted: 07/27/2021] [Indexed: 11/16/2022]
Abstract
Background: Squamous carcinomas of the uterine cervix often carry mutations of the gene encoding for the catalytic sub-unit of kinase PI3K, PIK3CA. The locus of this gene at chromosome 3q26 and neighboring loci are also commonly amplified. The landscape of 3q26-amplified cases have not been previously characterized in detail in cervical cancer. Methods: Published genomic data and associated clinical data from TCGA cervical cancer cohort were analyzed at cBioportal for amplifications in genes at 3q26. The clinical and molecular characteristics of the group of patients with 3q26 amplifications was compared with the group without 3q26 amplifications. Comparative prevalence of amplification and expression of genes at 3q26 in amplified squamous cervical cancer cases were surveyed as well as 3q26 amplifications in cervical cancer cell line databases. Results: Amplification of 3q26 locus is a prevalent molecular lesion in cervical squamous cell carcinomas encountered in about 15% of cases in TCGA cohort of 247 patients. Cancer-related genes commonly amplified from 3q26 include PIK3CA, TBL1XR1, DCUN1D1, SOX2, MECOM, PRKCI, and TERC. Amplified cases do not completely overlap with PIK3CA mutant cases. Differences exist between 3q26-amplified and non-amplified carcinomas in the frequency of mutations and frequency of other amplifications. Most commonly over-expressed genes in 3q26 amplified cases include PIK3CA, TBL1XR1, DCUN1D1, and less commonly SOX2 and PRKCI. Conclusion: The subset of squamous cervical carcinomas with 3q26 amplifications is not overlapping with cancers carrying PIK3CA mutations and contains, besides PIK3CA, other cancer-associated genes that are over-expressed at the mRNA level, including TBL1XR1 and DCUN1D1. DCUN1D1, a regulator of SCF ubiquitin ligase activity, may be a relevant pathogenic player given the importance of ubiquitination and the proteasome in the disease. These observations could form the basis for therapeutic exploitation in this subset of squamous cervical carcinomas.
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Voutsadakis IA. Chromosome 20q11.21 Amplifications in Colorectal Cancer. Cancer Genomics Proteomics 2021; 18:487-496. [PMID: 33994370 DOI: 10.21873/cgp.20274] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Colorectal cancer is the most common gastrointestinal carcinoma in western countries. Prognosis of metastatic colorectal cancer has improved in the last decades, but the disease continues to carry an adverse outcome in most cases. An improved understanding of molecular pathogenesis has provided incremental benefits in survival outcomes with the introduction of targeted therapies for specific sub-types and gives hope for further improvements. MATERIALS AND METHODS Publicly available data from genomic series of colorectal cancer published by the TCGA were analyzed with the aim of characterizing the sub-set of colorectal cancers carrying amplifications of chromosome 20q11.21, compared with cancers with no amplifications in this locus. Associations of 20q11.21-amplified cancers with other molecular lesions commonly observed in colorectal cancer were explored. mRNA expression of genes from the locus in amplified cases was analyzed. An exploratory survival analysis was also performed. RESULTS Amplifications of genes at chromosome arm 20q are observed in 7% to 9% of colorectal cancers, representing the most commonly amplified loci in this type of cancer. The 20q11.21 presents the highest amplification rate in the 20q arm. 20q11.21 amplified cancers display concomitant mutations in the KRAS pathway and SMAD4 less often than non-amplified cancers. Mutations in DNA repair genes are also less often encountered in 20q11.21 amplified colorectal cancers than non-amplified ones. CONCLUSION Amplification of genes at locus 20q11.21, representing the most frequently amplified locus in colorectal cancers, is associated with specific molecular characteristics and may have therapeutic implications.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON, Canada; .,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada
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Voutsadakis IA. High Tumor Mutation Burden and Other Immunotherapy Response Predictors in Breast Cancers: Associations and Therapeutic Opportunities. Target Oncol 2021; 15:127-138. [PMID: 31741177 DOI: 10.1007/s11523-019-00689-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The recent development of effective immunotherapies with immune checkpoint inhibitors for the treatment of cancer has rekindled the interest for the immune system and its activation for an anti-cancer response. At the same time, it has become evident that not all types of cancers respond equally to these treatments, and even within the same tumor type only a subset of patients derive clinical benefit. Biomarkers predictive of response to immunotherapy have been sought and in certain occasions incorporated in the indication for treatment. These include expression of PD-L1 and defects in DNA mismatch repair (MMR). OBJECTIVE Tumor mutation burden (TMB) has been associated with response to immune checkpoint inhibitors. The current investigation examines TMB as a biomarker of response to immunotherapy in breast cancer. PATIENTS AND METHODS Publicly available data from the breast cancer study of The Cancer Genome Atlas (TCGA) and the METABRIC study were analyzed. Parameters examined included the TMB and specific mutations that may impact on TMB. In addition, correlations with breast cancer sub-types were investigated. RESULTS The percentage of breast cancers with high TMB (more than 192 mutations per sample) was low (3.5-4.6%) in luminal and triple-negative cancers and higher (14.1%) in the HER2-positive subset. Almost all cancers with high TMB had defects in MMR proteins or the replicative polymerases POLE and POLD1. CONCLUSIONS Small sub-sets of breast cancers with high TMB exist and may present an opportunity for effective immunotherapeutic targeting.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, ON, P6B 0A8, Canada. .,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada.
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The Landscape of PIK3CA Mutations in Colorectal Cancer. Clin Colorectal Cancer 2021; 20:201-215. [PMID: 33744168 DOI: 10.1016/j.clcc.2021.02.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/18/2021] [Accepted: 02/14/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colorectal cancer is one of the most common malignancies in both men and women. Despite progress in the treatment of the disease, metastatic colorectal cancer remains lethal with a median survival slightly surpassing 2 years and commonly for some cases a more aggressive course. New therapies are urgently needed based on a better understanding of the molecular pathogenesis of the disease. METHODS The focus of this investigation is the PIK3CA gene, encoding the alpha catalytic subunit of the enzyme phosphatidylinositol-3 kinase (PI3K). Publicly available data from 3 extensive published series of colorectal carcinomas were analyzed to define the molecular landscape of colorectal adenocarcinomas with and without mutations of PIK3CA. An analysis for discovery of associations with alterations in other critical genes and pathways involved in colorectal cancer was performed. The total mutation burden (TMB) and copy number alteration burden of colorectal cancers with and without mutations of PIK3CA, as well as prognostic implications of alterations of the gene for survival, were examined. RESULTS Mutations in PIK3CA are observed in 20% to 25% of colorectal cancers. PIK3CA represents one of the most frequently mutated oncogenes in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β-catenin pathway. In addition, PIK3CA mutated colorectal cancers display a higher TMB than nonmutated cancers. CONCLUSION Frequent mutations of PIK3CA gene in colorectal carcinomas may represent an opportunity for targeted therapy combination development inhibiting both the PI3K kinase itself and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity, which could be augmented by other targeted therapies.
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HCMV-Mediated Interference of Bortezomib-Induced Apoptosis in Colon Carcinoma Cell Line Caco-2. Viruses 2021; 13:v13010083. [PMID: 33435377 PMCID: PMC7827311 DOI: 10.3390/v13010083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 11/18/2022] Open
Abstract
Human cytomegalovirus (HCMV) has been implicated in the development of human malignancies, for instance in colon cancer. Proteasome inhibitors were developed for cancer therapy and have also been shown to influence HCMV infection. The aim of this study was to investigate if proteasome inhibitors have therapeutic potential for colon carcinoma and how this is influenced by HCMV infection. We show by immunofluorescence and flow cytometry that the colon carcinoma cell line Caco-2 is susceptible to HCMV infection. Growth curve analysis as well as protein expression kinetics and quantitative genome analysis further confirm these results. HCMV has an anti-apoptotic effect on Caco-2 cells by inhibiting very early events of the apoptosis cascade. Further investigations showed that HCMV stabilizes the membrane potential of the mitochondria, which is typically lost very early during apoptosis. This stabilization is resistant to proteasome inhibitor Bortezomib treatment, allowing HCMV-infected cells to survive apoptotic signals. Our findings indicate a possible role of proteasome inhibitors in colon carcinoma therapy.
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Voutsadakis IA. Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets. Cancer Manag Res 2020; 12:10423-10437. [PMID: 33116896 PMCID: PMC7585777 DOI: 10.2147/cmar.s249540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 09/25/2020] [Indexed: 01/09/2023] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer and the most lethal gynecologic malignancy due to advanced stage at presentation. Recent years have witnessed progress in the therapy of HGSOC with the introduction of PARP (poly-adenosine diphosphate ribose polymerase) inhibitors and the anti-angiogenic monoclonal antibody bevacizumab to the backbone of chemotherapy or as maintenance therapy after chemotherapy. The improved molecular understanding of ovarian cancer pathogenesis, which has brought these therapies into the clinic, aspires to extend the boundaries of therapies through elucidation of other molecular aspects of ovarian carcinogenesis. This accumulating knowledge has started to be translated to additional targeted therapies that are in various stages of development. These include inhibitors of the function of other proteins involved in homologous recombination deficiency (HRD), such as WEE1 kinase, ATM/ATR kinases and CDK12 inhibitors. Despite disappointing results with immune checkpoint inhibitors monotherapy, harnessing the immune system in HGSOC with combination therapies that promote antigen production and immune cell activation is an avenue being explored. This paper examines arising HGSOC therapies based on molecular understanding of pathogenesis.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada
- Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada
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Voutsadakis IA. Low-grade serous ovarian carcinoma: an evolution toward targeted therapy. Int J Gynecol Cancer 2020; 30:1619-1626. [PMID: 31780569 DOI: 10.1136/ijgc-2019-000832] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/16/2019] [Accepted: 09/24/2019] [Indexed: 11/04/2022] Open
Abstract
Low-grade serous ovarian carcinoma and its high-grade serous ovarian carcinoma counterpart differ in their precursor lesions, molecular profile, natural history, and response to therapies. As such, low-grade serous ovarian carcinoma needs to be studied separately from high-grade serous ovarian carcinoma, despite challenges stemming from its rarity. A deeper understanding of the pathogenesis of low-grade serous ovarian carcinoma and the most common molecular defects and pathways involved in the carcinogenesis of the ovarian epithelium from normal to serous borderline ovarian tumors to low-grade serous ovarian carcinoma will help develop better therapies. By adopting targeted approaches there may be an opportunity to integrate novel therapies without the need for robust numbers in clinical trials. This manuscript will discuss low-grade serous ovarian carcinoma and focus on the arising treatments being developed with an improved understanding of the pathogenesis of this disease.
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Affiliation(s)
- Ioannis A Voutsadakis
- Section of Internal Medicine Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada
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A Driver Never Works Alone-Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer. Cancers (Basel) 2020; 12:cancers12061532. [PMID: 32545208 PMCID: PMC7353041 DOI: 10.3390/cancers12061532] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
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Voutsadakis IA. A role for Follistatin-like protein 1 (FSTL1) in colorectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:155. [PMID: 32309304 PMCID: PMC7154426 DOI: 10.21037/atm.2020.01.112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada.,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada
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Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat 2020; 48:100663. [DOI: 10.1016/j.drup.2019.100663] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/01/2019] [Accepted: 11/03/2019] [Indexed: 02/07/2023]
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Croft B, Reed M, Patrick C, Kovacevich N, Voutsadakis IA. Diabetes, Obesity, and the Metabolic Syndrome as Prognostic Factors in Stages I to III Colorectal Cancer Patients. J Gastrointest Cancer 2019; 50:221-229. [PMID: 29335847 DOI: 10.1007/s12029-018-0056-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Attempts to introduce prognostic factors for survival outcomes in localized colorectal cancer patients receiving surgical treatment with or without adjuvant therapies, beyond the classic staging parameters, have been met with limited success. Obesity and diabetes mellitus are among the conditions that predispose to colorectal cancer but their value as prognostic markers once the disease is diagnosed is controversial. PATIENTS AND METHODS This study examines the prognostic value of the components of metabolic syndrome in a retrospective series of colorectal cancer patients with stages I to III disease followed in a single center. RESULTS Among the four components of the metabolic syndrome, only diabetes was independently associated with progression-free survival (PFS) while obesity, hypertension, and dyslipidemia were not. No associations of the metabolic syndrome (MS) or its components with overall survival (OS) were observed in multivariate analysis. CONCLUSION These data pinpoint to diabetes mellitus (DM) as a possible prognostic factor for PFS in localized colorectal cancer and further cast doubt for the value of obesity as measured by body mass index (BMI) on local stage colorectal cancer prognosis.
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Affiliation(s)
- Brianna Croft
- Clinical Trials Unit, Sault Area Hospital, Sault Ste Marie, Ontario, Canada
| | - Melissa Reed
- Clinical Trials Unit, Sault Area Hospital, Sault Ste Marie, Ontario, Canada
| | - Caitlyn Patrick
- Clinical Trials Unit, Sault Area Hospital, Sault Ste Marie, Ontario, Canada
| | - Natalie Kovacevich
- Clinical Trials Unit, Sault Area Hospital, Sault Ste Marie, Ontario, Canada
| | - Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, Ontario, P6B 0A8, Canada.
- Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Voutsadakis IA. The pluripotency network in colorectal cancer pathogenesis and prognosis: an update. Biomark Med 2019; 12:653-665. [PMID: 29944017 DOI: 10.2217/bmm-2017-0369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Stemness characteristics are defining properties of cancer initiating cells and are associated with the ability to metastasize and survive in hostile environments. Establishment of the stem cell network depends on the action of a set of core transcription factors that work in concert with other ancillary proteins that are also important during embryonic development. New data consolidate the role of core pluripotency transcription factors OCT4, SOX2 and NANOG as adverse prognostic factors in colorectal cancer. mRNA-binding proteins LIN28 and Musashi, that are associated with stemness, and epigenetic modifiers such as de-acetylase SIRT1 may also have prognostic value in colorectal cancer. This paper provides an update of the stem cell factors in the pathogenesis and prognosis of colorectal cancer.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, Ontario, Canada.,Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada
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Karpisheh V, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Ghalamfarsa G, Sabz G, Yousefi M, Yousefi B, Jadidi-Niaragh F. Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat 2019; 144:106338. [PMID: 31100474 DOI: 10.1016/j.prostaglandins.2019.106338] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/30/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Although colon cancer is one of the most important triggers of cancer related mortality, a few therapeutic options exist for this disease, including combination chemotherapy, anti-EGFR and anti-angiogenic agents. However, none of these therapeutics are fully effective for complete remission, and this issue needs further investigations, particularly in the patients with advanced disease. It has been shown that colon carcinogenesis process is associated with upregulation of prostaglandin (PG) levels. Moreover, conversion of pre-malignant cells to malignant was also related with increased generation of PGs in susceptible subjects. Among the prostanoids, PGE2 is the most important produced member which generated in high levels by colon tumor cells. Generation of PGE2 by action of cyclooxygenase (COX)-2 can promote growth and development, resistance to apoptosis, proliferation, invasion and metastasis, angiogenesis and drug resistance in colon cancer. Increased levels of PGE2 and COX-2 in colon cancer is reported by various investigators which was associated with disease progression. It is suggested that there is a positive feedback loop between COX-2 and PGE2, in which function of COX-2 induces generation of PGE2, and upregulation of PGE2 increases the expression of COX-2 in colon cancer. Although an existence of this feedback loop is well-documented, its precise mechanism, signaling pathways, and the particular E-type prostanoid (EP) receptor mediating this feedback are elusive. Therefore, it seems that targeting COX-2/PGE2/EP receptors may be supposed as a potent therapeutic strategy for treatment of colon cancer. In this review, we try to clarify the role of PGE2 in cancer progression and its targeting for treatment of colon cancer.
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Affiliation(s)
- Vahid Karpisheh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Nikkhoo
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Afshin Namdar
- Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2E1 Canada
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Gholamabas Sabz
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Reed M, Patrick C, Croft B, Walde N, Voutsadakis IA. The metabolic syndrome and its components as prognostic factors in metastatic colorectal cancer. Indian J Gastroenterol 2019; 38:15-22. [PMID: 30701442 DOI: 10.1007/s12664-018-0923-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 11/30/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Components of the metabolic syndrome (MetS) are involved in colorectal cancer development and the incidence of the disease is higher in obese and diabetic patients. Nevertheless, the value of these diseases or the MetS as a whole as prognostic markers once colorectal cancer is diagnosed is controversial. METHODS Patients with metastatic colorectal cancer treated in our center over a 6-year period were reviewed and data on baseline characteristics of the patients and their cancers were extracted. Data on the presence and pharmacologic treatments of the four components of the MetS (obesity, diabetes, hypertension, and dyslipidemia) were also recorded. Overall survival (OS) and progression-free survival (PFS), Kaplan-Meier curves of the various groups were constructed and compared with the log-rank test. RESULTS One hundred and twenty-three patients were included in the analysis. The prevalence of the four MetS components was 66.1% for overweight/obesity, 25.2% for diabetes, 61% for hypertension, and 41.5% for dyslipidemia. Among the four components of the metabolic syndrome, none was associated with either PFS or OS. Diabetes tended to approach significance for PFS (p = 0.08). The MetS as a whole did not influence survival outcome. MetS was not prognostic even if the overweight category was not considered as a positive element of the syndrome. CONCLUSION These data suggest that diabetes or other metabolic syndrome elements are not prognostic factors for PFS or OS in metastatic colorectal cancer. Further investigation may be warranted with a focus on refinement of the metabolic evaluation.
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Affiliation(s)
- Melissa Reed
- Clinical Trials Unit, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada
| | - Caitlyn Patrick
- Clinical Trials Unit, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada
| | - Brianna Croft
- Clinical Trials Unit, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada
| | - Natalie Walde
- Clinical Trials Unit, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada
| | - Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, P6B 0A8, Canada. .,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Voutsadakis IA. HER2 in stemness and epithelial-mesenchymal plasticity of breast cancer. Clin Transl Oncol 2018; 21:539-555. [PMID: 30306401 DOI: 10.1007/s12094-018-1961-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023]
Abstract
Breast cancer had been the first non-hematologic malignancy where sub-types based on molecular characterization had entered clinical practice. HER2 over-expression, due to either gene amplification or protein up-regulation, defines one of these sub-types and is clinically exploited by addition of HER2-targeted treatments to the regimens of treatment. Nevertheless, in many occasions HER2-positive cancers are resistant or become refractory to these therapies. Several mechanisms, such as activation of alternative pathways or loss of expression of the receptor in cancer cells, have been proposed as the cause of these therapeutic failures. Cancer stem cells (CSCs, alternatively called tumor-initiating cells) comprise a small percentage of the tumor cells, but are capable of reconstituting and propagating tumors due to their superior intrinsic capacity for regeneration, survival and resistance to therapies. CSCs possess circuits enabling epigenetic plasticity which endow them with the ability to alternate between epithelial and mesenchymal states. This paper will discuss the expression and regulation of HER2 in CSCs of the different sub-types of breast cancer and relationships of the receptor with both the circuits of stemness and epithelial-mesenchymal plasticity. Therapeutic repercussions of the relationship of HER2-initiated signaling with stemness networks will also be proposed.
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Affiliation(s)
- I A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste. Marie, ON, P6B 0A8, Canada. .,Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada.
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Voutsadakis IA. Obesity and diabetes as prognostic factors in patients with colorectal cancer. Diabetes Metab Syndr 2017; 11 Suppl 1:S109-S114. [PMID: 27989518 DOI: 10.1016/j.dsx.2016.12.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 12/12/2016] [Indexed: 12/12/2022]
Abstract
Colorectal carcinoma is one of the most prevalent cancer types for both men and women. Prognosis of the disease is mostly defined by the stage. Localized disease has a better prognosis especially in earlier stages I and II. In addition most patients with more advanced localized stage III disease are expected to survive with a combination of surgery and adjuvant treatments. Progress in treatment of metastatic disease has led to median survivals exceeding 2 years and a minority of oligometastatic patients may survive even longer or be cured with multimodality therapy. Besides stage of the disease few prognostic factors are available to guide informative discussions with patients or guide therapeutic decisions. One area of research that may provide information in this direction is comorbidity conditions of the metabolic syndrome spectrum. Despite a significant body of literature investigating elements of the metabolic syndrome such as obesity and diabetes in isolation as risk and prognostic factors in colorectal cancer, a more restricted amount of research is dealing with the combination of these two factors as prognosticators of colorectal cancer. This paper will discuss published data on these factors and specifically their combination in the prognosis of colorectal cancer and will address some of their pathogenesis and therapy implications.
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Affiliation(s)
- Ioannis A Voutsadakis
- Division of Medical Oncology, Department of Internal Medicine, Sault Area Hospital, Sault Ste Marie, Ontario, Canada; Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Hopirtean C, Ciuleanu T, Cainap C, Todor N, Nagy V. BODY MASS INDEX AS A PROGNOSTIC FACTOR FOR DISEASE PROGRESSION IN PATIENTS WITH METASTATIC COLORECTAL CANCER TREATED WITH BEVACIZUMAB BASED SYSTEMIC THERAPY. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2017; 13:425-430. [PMID: 31149211 PMCID: PMC6516556 DOI: 10.4183/aeb.2017.425] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
CONTEXT Epidemiological data have shown that obesity increases the risk of developing colorectal cancer and also an increased body mass index (BMI) is associated with a worse prognosis. Bevacizumab based systemic therapy, an antiVEGF targeted therapy, is an important treatment option for metastatic colorectal cancer (mCRC) patients. Obesity is associated with high level of vascular endothelial growth factor (VEGF), that might provoke resistance to antiVEGF monoclonal antibody. OBJECTIVE To evaluate the efficacy in terms of progression free survival (PFS) and overall survival (OS) of bevacizumab systemic therapy in patients with mCRC. DESIGN Retrospective cohort, single center study. SUBJECTS AND METHODS Between January 2007 and December 2012, 112 patients with mCRC, who followed bevacizumab based systemic therapy in the "Ion Chiricuta" Oncology Institute in Cluj-Napoca, were included in our analysis. RESULTS Values of BMI ≥ or <27 kg/sqm was found that PFS is statistically significant superior in patients with BMI<27 kg/sqm (n=77) than in those with BMI ≥ 27 kg/sqm (n=35), 24 months versus 17.9 months (p = 0.04). Five years OS was not influenced by the BMI, 35% vs 30% (p=0.29). In patients with liver metastases with values of BMI ≥ 27 kg/sqm have PFS lower than patients with a BMI <27 kg/sqm, 17.5 months versus 24.5 months (p = 0.02). Five years OS was not influenced by the BMI, 39% (BMI <27 kg/sqm) vs. 22% (BMI ≥ 27 kg/sqm) (p = 0.09). CONCLUSIONS This study demonstrated the negative influence of BMI on both PFS on the entire sample of patients and in patients with liver metastases only, BMI cut-off value proved to be 27 kg/square meter and shows that the BMI may be an important prognostic factor with a high clinical relevance in patients with mCRC.
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Affiliation(s)
- C. Hopirtean
- “Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
| | - T. Ciuleanu
- “Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
- “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - C. Cainap
- “Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
- “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - N. Todor
- “Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
| | - V. Nagy
- “Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
- “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Hsu HH, Lin YM, Shen CY, Shibu MA, Li SY, Chang SH, Lin CC, Chen RJ, Viswanadha VP, Shih HN, Huang CY. Prostaglandin E2-Induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells. Int J Mol Sci 2017; 18:E1132. [PMID: 28587064 PMCID: PMC5485956 DOI: 10.3390/ijms18061132] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/12/2017] [Accepted: 05/15/2017] [Indexed: 12/11/2022] Open
Abstract
Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 μM) promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, β-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF-4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the β-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells.
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Affiliation(s)
- Hsi-Hsien Hsu
- Division of Colorectal Surgery, Mackay Memorial Hospital, Freshwater 25160, Taiwan.
- Mackay Medicine, Nursing and Management College, Taipei 10449, Taiwan.
| | - Yueh-Min Lin
- Department of pathology, Changhua Christian Hospital, Changhua 500, Taiwan.
- Medical Technology, Jen-The Junior College of Medicine, Nursing and Management, Miaoli 35664, Taiwan.
| | - Chia-Yao Shen
- Department of Nursing, Mei Ho University, Pingguang Road, Pingtung 912, Taiwan.
| | - Marthandam Asokan Shibu
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
| | - Shin-Yi Li
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
| | - Sheng-Huang Chang
- Tsao-Tun Psychiatric Center, Department of Health, Executive Yuan, Taipei 10058, Taiwan.
| | - Chien-Chung Lin
- Orthopaedic Department, Armed Forces General Hospital, Taichung 404, Taiwan.
| | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | | | - Hui-Nung Shih
- Division of Colorectal Surgery, Mackay Memorial Hospital, Freshwater 25160, Taiwan.
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
| | - Chih-Yang Huang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
- Graduate Institute of Chinese Medical Science, China Medical University, Taichung 40402, Taiwan.
- Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
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Hsu HH, Chen MC, Day CH, Lin YM, Li SY, Tu CC, Padma VV, Shih HN, Kuo WW, Huang CY. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation. World J Gastroenterol 2017; 23:1171-1179. [PMID: 28275297 PMCID: PMC5323442 DOI: 10.3748/wjg.v23.i7.1171] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To identify potential anti-cancer constituents in natural extracts that inhibit cancer cell growth and migration.
METHODS Our experiments used high dose thymoquinone (TQ) as an inhibitor to arrest LoVo (a human colon adenocarcinoma cell line) cancer cell growth, which was detected by cell proliferation assay and immunoblotting assay. Low dose TQ did not significantly reduce LoVo cancer cell growth. Cyclooxygenase 2 (COX-2) is an enzyme that is involved in the conversion of arachidonic acid into prostaglandin E2 (PGE2) in humans. PGE2 can promote COX-2 protein expression and tumor cell proliferation and was used as a control.
RESULTS Our results showed that 20 μmol/L TQ significantly reduced human LoVo colon cancer cell proliferation. TQ treatment reduced the levels of p-PI3K, p-Akt, p-GSK3β, and β-catenin and thereby inhibited the downstream COX-2 expression. Results also showed that the reduction in COX-2 expression resulted in a reduction in PGE2 levels and the suppression of EP2 and EP4 activation. Further analysis showed that TG treatment inhibited the nuclear translocation of β-catenin in LoVo cancer cells. The levels of the cofactors LEF-1 and TCF-4 were also decreased in the nucleus following TQ treatment in a dose-dependent manner. Treatment with low dose TQ inhibited the COX-2 expression at the transcriptional level and the regulation of COX-2 expression efficiently reduced LoVo cell migration. The results were further verified in vivo by confirming the effects of TQ and/or PGE2 using tumor xenografts in nude mice.
CONCLUSION TQ inhibits LoVo cancer cell growth and migration, and this result highlights the therapeutic advantage of using TQ in combination therapy against colorectal cancer.
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Voutsadakis IA. Pluripotency transcription factors in the pathogenesis of colorectal cancer and implications for prognosis. Biomark Med 2016; 9:349-61. [PMID: 25808439 DOI: 10.2217/bmm.15.4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The cancer stem cell hypothesis argues that cancers depend on a specific type of cells, representing usually a small percentage of the total cancer cell population, termed cancer stem cells (or tumor-initiating cells) for their development and propagation. In colorectal cancer these cells express specific surface proteins such as CD133 and CD44 and can recapitulate the whole tumor. Besides expression of these surface markers, stem cells are associated with a network of pluripotency transcription factors, such as Oct4 and Sox2, which is present in them. Pluripotency factors are normally active in early development and characterize primitive cells, able to give rise to all different cell and tissue types of the three embryonic layers. In this review I will discuss the relationship of these factors with pathogenic lesions in colorectal cancer and their prognostic implications.
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Spirina LV, Usynin EA, Kondakova IV, Yurmazov ZA, Slonimskaya EM. Molecular Markers of Kidney Cancer Progression, Association with Efficiency of Pazopanib Therapy. ACTA ACUST UNITED AC 2015. [DOI: 10.4236/jbise.2015.811072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Lichti CF, Wildburger NC, Emmett MR, Mostovenko E, Shavkunov AS, Strain SK, Nilsson CL. Post-translational Modifications in the Human Proteome. TRANSLATIONAL BIOINFORMATICS 2014. [DOI: 10.1007/978-94-017-9202-8_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Swami U, Goel S, Mani S. Therapeutic targeting of CPT-11 induced diarrhea: a case for prophylaxis. Curr Drug Targets 2013; 14:777-97. [PMID: 23597015 DOI: 10.2174/1389450111314070007] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 03/23/2013] [Accepted: 04/04/2013] [Indexed: 12/14/2022]
Abstract
CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (β-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents.
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Affiliation(s)
- Umang Swami
- Internal Medicine, St. Barnabas Hospital, Bronx, NY 10457, USA
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Vlachostergios PJ, Voutsadakis IA, Papandreou CN. The shaping of invasive glioma phenotype by the ubiquitin-proteasome system. CELL COMMUNICATION & ADHESION 2013; 20:87-92. [PMID: 24004256 DOI: 10.3109/15419061.2013.833192] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Protein degradation is an indispensable process for cells which is often deregulated in various diseases, including malignant conditions. Depending on the specific cell type and functions of expressed proteins, this aberration may have different effects on the determination of malignant phenotypes. A discrete, inherent feature of malignant glioma is its profound invasive and migratory potential, regulated by the expression of signaling and effector proteins, many of which are also subjected to post-translational regulation by the ubiquitin-proteasome system (UPS). Here we provide an overview of this connection, focusing on important pro-invasive protein signals targeted by the UPS.
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Affiliation(s)
- Panagiotis J Vlachostergios
- Faculty of Medicine, Department of Medical Oncology, University of Thessaly University Hospital of Larissa , Larissa , Greece
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Spirina LV, Kondakova IV, Choynzonov EL, Chigevskaya SY, Shishkin DA, Kulbakin DY. Expression of vascular endothelial growth factor and transcription factors HIF-1, NF-kB expression in squamous cell carcinoma of head and neck; association with proteasome and calpain activities. J Cancer Res Clin Oncol 2013; 139:625-33. [PMID: 23269488 DOI: 10.1007/s00432-012-1366-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 11/08/2012] [Indexed: 12/23/2022]
Abstract
INTRODUCTION The transcription factors NF-kB, HIF-1 and vascular endothelial growth factors (VEGF) are known to play an important role in pathogenesis of squamous cell carcinoma of head and neck (SCCHN). PURPOSE The aim of the study was to determine the NF-kB, HIF-1 and VEGF, expression their characteristics in squamous cell carcinoma of head and neck. METHODS Transcription factors and VEGF expression were measured by ELISA kits. Proteasome and calpain activity were determined using specific fluorogenic substrate. Proteasome subunits composition was measured by Western blot analysis. RESULTS In the present study, we revealed the connection between SCCHN lymphogenous metastasis development and NF-kB p50 expression. An increase in total, 26S and 20S proteasome activities and calpain activity was observed in cancer tissues in comparison with agreed standard (non-transformed tissue). The dynamics of changes in proteasome activity and proteasome subunits content during lymph nodes metastasis development had a complex pattern. Nonparametric analysis of variance showed the connection between the extent of metastatic affection of regional lymph nodes, total proteasome activity and LMP2 expression. Proteasome and calpain systems corresponded and interacted with each other. We also revealed a positive correlation between the NF-kB p65 and p50 expression and proteasome activity. CONCLUSION Taken together, our results suggest that above mentioned transcription factors and intracellular proteolytic systems are involved in SCCHN progression and metastasis. Moreover, the opportunity of transcription factors regulation by proteasome takes place in oncogenesis of SCCHN. The results provide a basis for new prognostic tests and development of novel targeted therapy.
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Affiliation(s)
- Liudmila V Spirina
- Cancer Research Institute, Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Russian Federation.
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Kenney B, Deng Y, Mitchell K. Expression of p27, COX-2, MLH1, and MSH2 in young patients with colon carcinoma and correlation with morphologic findings. Hum Pathol 2012; 44:591-7. [PMID: 23084580 DOI: 10.1016/j.humpath.2012.07.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 07/01/2012] [Accepted: 07/05/2012] [Indexed: 11/24/2022]
Abstract
Despite an overall decrease in colorectal carcinoma incidence, rates of colorectal carcinoma have increased substantially in patients aged less than 40 years. Several authors have characterized morphologic features of colorectal carcinoma in young patients, with variable results. To date, there has been 1 detailed molecular and immunohistochemical study in young patients with colorectal carcinoma. We sought to expand the data regarding young patients with colorectal carcinoma by a detailed assessment of morphologic features and by assaying expression of p27, COX-2, MLH1, and MSH2, markers with prognostic or therapeutic implications in colorectal carcinoma. We searched our pathology database from 1985 to 2009 and, after exclusion of cases with insufficient data or neoadjuvant therapy, identified a study population of 23 patients aged 40 or younger, 35 patients between 41 and 49 years of age, and a control group of 83 colorectal carcinoma patients aged 50 or older. Younger patients had higher tumor grade (P = .0085), with a trend toward mucinous differentiation and lymphovascular and perineural invasion. Loss of MSH2 was more prominent in younger patients (P = .02). Loss of p27 expression was not associated with age, but was associated with higher tumor stage (P = .0278), mucinous/signet ring differentiation (P = .0185), loss of either MLH1 or MSH2 (P = .0035), and larger tumor size (P = .0019). There was a trend toward lower COX-2 expression in younger patients, with less COX-2 expression relative to previously published data. Our findings support some prior reports regarding morphologic features in colorectal carcinoma in young patients and provide novel data on expression of several markers in this population.
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Affiliation(s)
- Barton Kenney
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
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Stravodimou A, Mazzoccoli G, Voutsadakis IA. Peroxisome proliferator-activated receptor gamma and regulations by the ubiquitin-proteasome system in pancreatic cancer. PPAR Res 2012; 2012:367450. [PMID: 23049538 PMCID: PMC3459232 DOI: 10.1155/2012/367450] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/13/2012] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is one of the most lethal forms of human cancer. Although progress in oncology has improved outcomes in many forms of cancer, little progress has been made in pancreatic carcinoma and the prognosis of this malignancy remains grim. Several molecular abnormalities often present in pancreatic cancer have been defined and include mutations in K-ras, p53, p16, and DPC4 genes. Nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARγ) has a role in many carcinomas and has been found to be overexpressed in pancreatic cancer. It plays generally a tumor suppressor role antagonizing proteins promoting carcinogenesis such as NF-κB and TGFβ. Regulation of pathways involved in pancreatic carcinogenesis is effectuated by the Ubiquitin Proteasome System (UPS). This paper will examine PPARγ in pancreatic cancer, the regulation of this nuclear receptor by the UPS, and their relationship to other pathways important in pancreatic carcinogenesis.
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Affiliation(s)
- Athina Stravodimou
- Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, BH06, Bugnon 46, 1011 Lausanne, Switzerland
| | - Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
| | - Ioannis A. Voutsadakis
- Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, BH06, Bugnon 46, 1011 Lausanne, Switzerland
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Kondakova IV, Spirina LV, Shashova EE, Koval' VD, Kolomiets LA, Chernysheva AL, Slonimskaia EM. [Proteasome activity in tumors of female reproductive system]. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2012; 38:106-10. [PMID: 22792713 DOI: 10.1134/s106816201201013x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Proteasomes (multiproteinase protein complexes) are known to play an important role in cancer pathogenesis, however, few information about their activity in human tumor tissues is available so far. We studied chymotrypsin-like activity of proteasomes in tissues of breast cancer (BC) and endometrial cancer (EC). The chymotrypsin-like total proteasome activity and the 20S and 26S proteasome activity in malignant tissues were shown to be significantly higher in malignant tumors than in normal tissues. No increase in proteasome activity was registered with larger tumor size in both BC and EC, whereas proteasome activity was changed with respect to the extent of tumor involvement. In breast cancer tissues, significant reductions in the total and the 26S proteaome activities were observed in tumors with regional lymph node metastases as compared to tumors without metastases. In endometrial cancer tissues, the total proteasome activity and the 20S and 26S proteasome activities were increased as the depth of myometrial invasion. The data obtained indicate that the proteasome acyivity is significantly changed in the process of cancerogenesis and further study is needed to develop new additional prognostic criteria and effective anti-tumor agents in molecular-directed therapy.
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Voutsadakis IA. Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities. Clin Transl Oncol 2012; 14:243-53. [PMID: 22484631 DOI: 10.1007/s12094-012-0792-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.
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Affiliation(s)
- I A Voutsadakis
- Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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McCawley N, Conlon S, Hector S, Cummins RJ, Dicker P, Johnston PG, Kay EW, McNamara DA, Prehn JHM, Concannon CG. Analyzing proteasomal subunit expression reveals Rpt4 as a prognostic marker in stage II colorectal cancer. Int J Cancer 2012; 131:E494-500. [PMID: 21960357 DOI: 10.1002/ijc.26468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 09/08/2011] [Indexed: 11/09/2022]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Early diagnosis and treatment of colorectal cancer is the key to improving survival rates and as such a need exists to identify patients who may benefit from adjuvant chemotherapy. The dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in oncogenesis and cancer cell survival, and proteasome inhibitors are in clinical use for a number of malignancies including multiple myeloma. In our study, we examined the protein expression of several key components of the UPS in colorectal cancer using immunohistochemistry to determine expression levels of ubiquitinylated proteins and the proteasomal subunits, 20S core and Rpt4 in a cohort of 228 patients with colon cancer. Multivariate Cox analysis revealed that neither the intensity of either ubiquitinylated proteins or the 20S core was predictive in either Stage II or III colon cancer for disease free survival or overall survival. In contrast, in Stage II patients increased Rpt4 staining was significantly associated with disease free survival (Cox proportional hazard ratio 0.605; p = 0.0217). Our data suggest that Rpt4 is an independent prognostic variable for Stage II colorectal cancer and may aid in the decision of which patients undergo adjuvant chemotherapy.
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Affiliation(s)
- Niamh McCawley
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
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Ammar HO, Ghorab M, Mostafa DM, Makram TS, Ali RM. Host–guest system of etodolac in native and modified β-cyclodextrins: preparation and physicochemical characterization. J INCL PHENOM MACRO 2012. [DOI: 10.1007/s10847-012-0223-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Voutsadakis IA. The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer. J Biomed Sci 2012; 19:67. [PMID: 22827778 PMCID: PMC3418218 DOI: 10.1186/1423-0127-19-67] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 07/09/2012] [Indexed: 02/08/2023] Open
Abstract
Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.
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Affiliation(s)
- Ioannis A Voutsadakis
- Centre Pluridisciplinaire d'Oncologie, BH06, Centre Hospitalier Universitaire Vaudois, Bugnon 46, Lausanne, 1011, Switzerland.
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Grande E, Earl J, Fuentes R, Carrato A. New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies. Expert Rev Anticancer Ther 2012; 12:457-467. [DOI: 10.1586/era.12.26] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Ubiquitination and the Ubiquitin-Proteasome System as regulators of transcription and transcription factors in epithelial mesenchymal transition of cancer. Tumour Biol 2012; 33:897-910. [PMID: 22399444 DOI: 10.1007/s13277-012-0355-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 02/09/2012] [Indexed: 02/06/2023] Open
Abstract
Epithelial to Mesenchymal Transition (EMT) in cancer is a process that allows cancer cells to detach from neighboring cells, become mobile and metastasize and shares many signaling pathways with development. Several molecular mechanisms which regulate oncogenic properties in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis through transcription factors or other mediators are also regulators of EMT. These pathways and downstream transcription factors are, in their turn, regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination, the covalent link of the small 76-amino acid protein ubiquitin to target proteins, serves as a signal for protein degradation by the proteasome or for other outcomes such as endocytosis, degradation by the lysosome or directing these proteins to specific cellular compartments. This review discusses aspects of the regulation of EMT by ubiquitination and the UPS and underlines its complexity focusing on transcription and transcription factors regulating EMT and are being regulated by ubiquitination.
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Huang CJ, Yang SH, Huang SM, Lin CM, Chien CC, Chen YC, Lee CL, Wu HH, Chang CC. A predicted protein, KIAA0247, is a cell cycle modulator in colorectal cancer cells under 5-FU treatment. J Transl Med 2011; 9:82. [PMID: 21619678 PMCID: PMC3126726 DOI: 10.1186/1479-5876-9-82] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 05/28/2011] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and the leading cause of cancer death. The identification of genes related to CRC is important for the development of successful therapies and earlier diagnosis. METHODS Molecular analysis of feces was evaluated as a potential method for CRC detection. Expression of a predicted protein with unknown function, KIAA0247, was found in feces evaluated using specific quantitative real-time polymerase chain reaction. Its cellular function was then analyzed using immunofluorescent staining and the changes in the cell cycle in response to 5-fluorouracil (5-FU) were assessed. RESULTS Gastrointestinal tissues and peripheral blood lymphocytes ubiquitously expressed KIAA0247. 56 CRC patients fell into two group categories according to fecal KIAA0247 mRNA expression levels. The group with higher fecal KIAA0247 (n=22; ≥0.4897) had a significantly greater five-year overall survival rate than the group with lower fecal KIAA0247 (n = 30; <0.4897) (66.0 ± 11.6%; p=0.035, log-rank test). Fecal expression of KIAA0247 inversely related to CRC tumor size (Kendall's tau-b=-0.202; p=0.047). Immunofluorescent staining revealed that the cytoplasm of CRC cells evenly expresses KIAA0247 without 5-FU treatment, and KIAA0247 accumulates in the nucleus after 40 μM 5-FU treatment. In HCT116 p53(-/-) cells, which lack p53 cell cycle control, the proportion of cells in the G2/M phase was larger (13%) in KIAA0247-silent cells than in the respective shLuc control (10%) and KIAA0247-overexpressing cells (7%) after the addition of low dose (40 μM) 5-FU. Expression of three cyclin genes (cyclin A2, cyclin B1, and cyclin B2) also downregulated in the cells overexpressing KIAA0247. CONCLUSIONS This is the first description of a linkage between KIAA0247 and CRC. The study's data demonstrate overexpression of KIAA0247 associates with 5-FU therapeutic benefits, and also identify the clinical significance of fecal KIAA0247 in CRC.
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Affiliation(s)
- Chi-Jung Huang
- School of Medicine, Fu Jen Catholic University, New Taipei 24205, Taiwan
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Voutsadakis IA, Patrikidou A, Tsapakidis K, Karagiannaki A, Hatzidaki E, Stathakis NE, Papandreou CN. Additive inhibition of colorectal cancer cell lines by aspirin and bortezomib. Int J Colorectal Dis 2010; 25:795-804. [PMID: 20397022 DOI: 10.1007/s00384-010-0939-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2010] [Indexed: 02/04/2023]
Abstract
PURPOSE To investigate the effect of cyclooxygenase-2 (Cox-2) inhibitor aspirin (acetylsalicylic acid, ASA) and proteasome inhibitor bortezomib in the proliferation and apoptosis of colorectal cancer cell lines. METHODS MTT assay, trypan blue exclusion and DNA fragmentation have been used to investigate cell proliferation and apoptosis in the presence of drugs. For the determination of Cox activity a colorimetric method was used. Western blotting was used for the measurement of the effect of the drugs in different proteins expression. RESULTS Bortezomib together with aspirin inhibit the growth of colorectal cancer cell lines HCT116, HT-29, and CaCo2 more than each drug alone. In the first two cell lines ASA inhibitory effects are Cox-2 independent because HCT116 cells do not express the enzyme while in HT-29 cells, Cox-2 has no activity as shown by a Cox activity assay. In CaCo2 cells that express enzymatically active Cox-2 this activity is inhibited by ASA. ASA is also able to suppress the increase in Cox-2 activity induced by bortezomib in these cells. Cell cycle inhibitors p21 and p27 are induced in the three cell lines by bortezomib and the combination treatment. Akt1 kinase is down-regulated in all three lines by the same treatments. Transcription factor NF-kappaB is retained in the cytoplasm by drug treatment in cell lines HCT116 and HT-29, a fact that may play a role in their pro-apoptotic activity. Pro-apoptotic bcl-2 family member, bad is down-regulated in cell lines HCT116 and CaCo2 by bortezomib treatment, a neoplasia-promoting event that is reversed by combination treatment. CONCLUSION The combination of bortezomib and ASA cooperates to decrease proliferation and induce apoptosis in three human colorectal cell lines with different genetic lesions. These effects are at least in some cases Cox-2 independent and involve common and diverse mechanisms in the three lines.
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The ubiquitin-proteasome system in prostate cancer and its transition to castration resistance. Urol Oncol 2010; 30:752-61. [PMID: 20580272 DOI: 10.1016/j.urolonc.2010.03.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Revised: 03/16/2010] [Accepted: 03/18/2010] [Indexed: 11/22/2022]
Abstract
Prostate cancer is the most common carcinoma in the male population. In its initial stage, the disease is androgen-dependent and responds therapeutically to androgen deprivation treatment but it usually progresses after a few years to an androgen-independent phase that is refractory to hormonal manipulations. The proteasome is a multi-unit protease system that regulates the abundance and function of a significant number of cell proteins, and its inhibition results in cancer cell growth inhibition and apoptosis and is already exploited in the clinic with the use of proteasome inhibitor bortezomib in multiple myeloma. In order to be recognized by the proteasome, a target protein needs to be linked to a chain of the small protein ubiquitin. In this paper, we review the role of ubiquitin-proteasome system (UPS) in androgen receptor-dependent transcription as well as in the castration resistant stage of the disease, and we discuss therapeutic opportunities that UPS inhibition offers in prostate cancer.
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Wu CH, Shih YW, Chang CH, Ou TT, Huang CC, Hsu JD, Wang CJ. EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells. Arch Toxicol 2010; 84:731-40. [PMID: 20571779 DOI: 10.1007/s00204-010-0562-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Accepted: 05/07/2010] [Indexed: 01/24/2023]
Abstract
Previous studies indicate that COX-2 and prostaglandin E(2) (PGE(2)) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE(2) receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP(1)/EP(4) were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3beta and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP(4) inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3beta/EP(4) PGE(2) receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.
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Affiliation(s)
- Cheng-Hsun Wu
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, Republic of China
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