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Das AS, Basu A, Mukhopadhyay R. Ribosomal proteins: the missing piece in the inflammation puzzle? Mol Cell Biochem 2025; 480:785-797. [PMID: 38951378 DOI: 10.1007/s11010-024-05050-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/09/2024] [Indexed: 07/03/2024]
Abstract
Ribosomal proteins (RPs) are constituents of macromolecular machinery, ribosome that translates genetic information into proteins. Besides ribosomal functions, RPs are now getting appreciated for their 'moonlighting'/extra-ribosomal functions modulating many cellular processes. Accumulating evidence suggests that a number of RPs are involved in inflammation. Though acute inflammation is a part of the innate immune response, uncontrolled inflammation is a driving factor for several chronic inflammatory diseases. An in-depth understanding of inflammation regulation has always been valued for the better management of associated diseases. Hence, this review first outlines the common livelihood of RPs and then provides a comprehensive account of five RPs that significantly contribute to the inflammation process. Finally, we discuss the possible therapeutic uses of RPs against chronic inflammatory diseases.
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Affiliation(s)
- Anindhya Sundar Das
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India.
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, 02912, USA.
| | - Anandita Basu
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, 02903, USA
| | - Rupak Mukhopadhyay
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India.
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2
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Wang L, Chen M, Ma Z, Zeng H, Xie B, Xu S. Exploring the Clinical Implications of RPL3 Presence in BRCA-Associated Cancers: Unraveling the Interplay With Cancer Immunity. Clin Med Insights Oncol 2024; 18:11795549241285387. [PMID: 39429685 PMCID: PMC11488323 DOI: 10.1177/11795549241285387] [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: 03/22/2024] [Accepted: 09/03/2024] [Indexed: 10/22/2024] Open
Abstract
Background Few studies have explored the expression profile of RPL3 in breast cancer (BRCA). Our research provided an in-depth analysis of RPL3 expression patterns in BRCA, highlighting its significance for therapy prediction and prognosis. Methods RPL3 was notably elevated in malignant cells, and its expression level was closely associated with tumor size and overall survival outcomes. Our study also identified RPL3-related terms and pathways and revealed a strong correlation between RPL3 expression and breast carcinoma immunity, demonstrating inconsistent expression levels in various immune cell lines. In addition, we examined the relationship between RPL3 expression and tumor mutational burden (TMB) in BRCA. To assess the clinical implications of BRCA chemotherapy, we investigated the correlation between RPL3 expression levels and drug sensitivity. Results Our findings suggest that RPL3 plays a critical role in the BRCA process and is associated with immune infiltration, indicating its potential as a novel immunotherapy target in BRCA treatment. Conclusions In summary, our research underscores the importance of RPL3 expression levels in tumorigenesis and its potential for guiding BRCA immunotherapy.
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Affiliation(s)
- Linyi Wang
- Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Minlong Chen
- Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Zhaosheng Ma
- Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Hanqian Zeng
- Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Bojian Xie
- Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shiwen Xu
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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Longobardi G, Moore TL, Conte C, Ungaro F, Satchi‐Fainaro R, Quaglia F. Polyester nanoparticles delivering chemotherapeutics: Learning from the past and looking to the future to enhance their clinical impact in tumor therapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1990. [PMID: 39217459 PMCID: PMC11670051 DOI: 10.1002/wnan.1990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/20/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Polymeric nanoparticles (NPs), specifically those comprised of biodegradable and biocompatible polyesters, have been heralded as a game-changing drug delivery platform. In fact, poly(α-hydroxy acids) such as polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and poly(ε-caprolactone) (PCL) have been heavily researched in the past three decades as the material basis of polymeric NPs for drug delivery applications. As materials, these polymers have found success in resorbable sutures, biodegradable implants, and even monolithic, biodegradable platforms for sustained release of therapeutics (e.g., proteins and small molecules) and diagnostics. Few fields have gained more attention in drug delivery through polymeric NPs than cancer therapy. However, the clinical translational of polymeric nanomedicines for treating solid tumors has not been congruent with the fervor or funding in this particular field of research. Here, we attempt to provide a comprehensive snapshot of polyester NPs in the context of chemotherapeutic delivery. This includes a preliminary exploration of the polymeric nanomedicine in the cancer research space. We examine the various processes for producing polyester NPs, including methods for surface-functionalization, and related challenges. After a detailed overview of the multiple factors involved with the delivery of NPs to solid tumors, the crosstalk between particle design and interactions with biological systems is discussed. Finally, we report state-of-the-art approaches toward effective delivery of NPs to tumors, aiming at identifying new research areas and re-evaluating the reasons why some research avenues have underdelivered. We hope our effort will contribute to a better understanding of the gap to fill and delineate the future research work needed to bring polyester-based NPs closer to clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
| | - Thomas Lee Moore
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Claudia Conte
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Francesca Ungaro
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Ronit Satchi‐Fainaro
- Department of Physiology and Pharmacology, Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- Sagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Fabiana Quaglia
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
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Chen G, Han R, Wang L, Ma W, Zhang W, Lu Z, Wang L. Establishment of patient-derived organoids and a characterization based drug discovery platform for treatment of gastric cancer. Cancer Cell Int 2024; 24:288. [PMID: 39143546 PMCID: PMC11323579 DOI: 10.1186/s12935-024-03460-9] [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: 02/02/2024] [Accepted: 07/25/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation. METHODS Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy. RESULTS We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib. CONCLUSION The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.
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Affiliation(s)
- Guo Chen
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China
| | - Ruidong Han
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Li Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China
| | - Wen Ma
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wenli Zhang
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Zifan Lu
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China.
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China.
| | - Lei Wang
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
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González-Arzola K. The nucleolus: Coordinating stress response and genomic stability. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195029. [PMID: 38642633 DOI: 10.1016/j.bbagrm.2024.195029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/25/2024] [Accepted: 04/12/2024] [Indexed: 04/22/2024]
Abstract
The perception that the nucleoli are merely the organelles where ribosome biogenesis occurs is challenged. Only around 30 % of nucleolar proteins are solely involved in producing ribosomes. Instead, the nucleolus plays a critical role in controlling protein trafficking during stress and, according to its dynamic nature, undergoes continuous protein exchange with nucleoplasm under various cellular stressors. Hence, the concept of nucleolar stress has evolved as cellular insults that disrupt the structure and function of the nucleolus. Considering the emerging role of this organelle in DNA repair and the fact that rDNAs are the most fragile genomic loci, therapies targeting the nucleoli are increasingly being developed. Besides, drugs that target ribosome synthesis and induce nucleolar stress can be used in cancer therapy. In contrast, agents that regulate nucleolar activity may be a potential treatment for neurodegeneration caused by abnormal protein accumulation in the nucleolus. Here, I explore the roles of nucleoli beyond their ribosomal functions, highlighting the factors triggering nucleolar stress and their impact on genomic stability.
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Affiliation(s)
- Katiuska González-Arzola
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Junta de Andalucía, Universidad Pablo de Olavide, 41092 Seville, Spain; Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain.
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Merlino F, Pecoraro A, Longobardi G, Donati G, Di Leva FS, Brignola C, Piccarducci R, Daniele S, Martini C, Marinelli L, Russo G, Quaglia F, Conte C, Russo A, La Pietra V. Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells. J Med Chem 2024; 67:1812-1824. [PMID: 38285632 DOI: 10.1021/acs.jmedchem.3c01312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 (1), the only known peptide acting through this mechanism. The new peptides, notably 3 and 9, showed lower IC50 values than 1. When incorporated into tumor-targeted biodegradable nanoparticles, these exhibited cytotoxicity against three different CRC cell lines. Notably, NPs/9 caused a significant increase in p53 levels associated with a strong increment of its main downstream target p21 inducing apoptosis. Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.
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Affiliation(s)
- Francesco Merlino
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Annalisa Pecoraro
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Giuseppe Longobardi
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Greta Donati
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | | | - Chiara Brignola
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Rebecca Piccarducci
- Department of Pharmacy, University of Pisa, via Bonanno, 6, 56126 Pisa, PI, Italy
| | - Simona Daniele
- Department of Pharmacy, University of Pisa, via Bonanno, 6, 56126 Pisa, PI, Italy
| | - Claudia Martini
- Department of Pharmacy, University of Pisa, via Bonanno, 6, 56126 Pisa, PI, Italy
| | - Luciana Marinelli
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Giulia Russo
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Fabiana Quaglia
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Claudia Conte
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Annapina Russo
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Valeria La Pietra
- Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, NA, Italy
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Rai S, Singh MP, Srivastava S. Integrated Analysis Identifies Novel Fusion Transcripts in Laterally Spreading Tumors Suggestive of Distinct Etiology Than Colorectal Cancers. J Gastrointest Cancer 2023; 54:913-926. [PMID: 36480069 DOI: 10.1007/s12029-022-00881-5] [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] [Accepted: 10/26/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Laterally spreading tumors (LSTs) of the colon and rectum are a class of abnormality which spreads laterally and appears ulcerated. They are a subclass of colorectal cancer (CRCs) with higher invasive potential than CRCs. Moreover, the etiology of LST still remains obscure. METHODS This study aimed to identify unique fusion transcript(s) in LSTs and evaluate their role in LST development and progression. RNA-Seq data for LST samples from the EMBL-EBI database were used to identify fusion transcripts. An integrated approach using Gene Ontology, pathway analysis, hub gene, and co-expression network analysis functionally characterized fusion transcripts to shed light upon the etiology of LSTs. RESULT We identified 48 unique fusion genes in LSTs. GO terms were enriched in mRNA metabolic (p ≤ 2.06E-06), mRNA stabilization (p ≤ 1.60E-05), in cytosol (1.20E-05), RBP (p ≤ 2.30E-04), and RNA binding activity (p ≤ 3.51E-08) processes. Pathway analysis revealed an inflammatory phenotype of LSTs suggesting a distinct etiology than CRCs as pathways were enriched in salmonella infection (p ≤ 4.41 e-03), proteoglycans in cancer (p ≤ 1.18 e-02), and insulin signaling (p ≤ 2.13 e-02). Our exclusion and inclusion criteria and hub gene analysis finally identified 9 hub genes. Co-expression analysis of hub genes identified the most significant transcription factors (NELFE, MYC, TAF1, MAX) and kinases (MAPK14, CSNK2A1, CDK1, MAPK1) which were implicated in various cancer pathways. Furthermore, an overall survival analysis of hub genes was performed. Our predefined criterion resulted in the enrichment of NPM1-PTMA (NPM1: p ≤ 0.005) and HIST1H2BO-YBX1 (YBX1: p ≤ 0.02) fusion transcripts, significantly associated with the patient's overall survival. CONCLUSION Our systematic analysis resulted in novel fusion genes in LSTs suggesting a different etiology than CRCs. Fusion transcripts were observed more frequently in non-granular LSTs suggestive of genetically more unstable than granular LST. We hypothesize that NPM1-PTMA and HIST1H2BO-YBX1 could be implicated in LST development and progression and may also serve as a prognostic or diagnostic biomarker in future for better management of LSTs.
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Affiliation(s)
- Sandhya Rai
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Uttar Pradesh, 211004, Prayagraj, India
| | - Manish Pratap Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Uttar Pradesh, 211004, Prayagraj, India
- CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Uttar Pradesh, 226031, Lucknow, India
| | - Sameer Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Uttar Pradesh, 211004, Prayagraj, India.
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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9
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Antitumor Effect of Cycloastragenol in Colon Cancer Cells via p53 Activation. Int J Mol Sci 2022; 23:ijms232315213. [PMID: 36499536 PMCID: PMC9737126 DOI: 10.3390/ijms232315213] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer cell (CRC) is the fourth most common cancer in the world. There are several chemotherapy drugs available for its treatment, though they have side effects. Cycloastragenol (CY) is a compound from Astragalus membranaceus (Fisch.) Bge known to be effective in aging, anti-inflammatory, anticancer, and anti-heart failure treatments. Although many studies have demonstrated the functions of CY in cancer cells, no studies have shown the effects of p53 in colon cancer cells. In this study, we found that CY reduces the viability of colon cancer cells in p53 wild-type cells compared to p53 null cells and HT29. Furthermore, CY induces apoptosis by p53 activation in a dose- and time-dependent manner. And it was confirmed that it affects the L5 gene related to p53. Additionally, CY enhanced p53 expression compared to when either doxorubicin or 5-FU was used alone. Altogether, our findings suggest that CY induces apoptosis via p53 activation and inhibits the proliferation of colon cancer cells. In addition, apoptosis occurs in colon cancer cells due to other factors. Moreover, CY is expected to have a combined effect when used together with existing treatments for colon cancer in the future.
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10
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Sang R, Deng F, Engel A, Goldys E, Deng W. Lipid-polymer nanocarrier platform enables X-ray induced photodynamic therapy against human colorectal cancer cells. Biomed Pharmacother 2022; 155:113837. [PMID: 36271586 DOI: 10.1016/j.biopha.2022.113837] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/26/2022] [Accepted: 10/06/2022] [Indexed: 11/16/2022] Open
Abstract
In this study, we brought together X-ray induced photodynamic therapy (X-PDT) and chemo-drug (5-FU) for the treatment on colorectal cancer cells. This was achieved by developing a lipid-polymer hybrid nanoparticle delivery system (FA-LPNPs-VP-5-FU). It was prepared by incorporating a photosensitizer (verteporfin), chemotherapy drug (5-FU) and a targeting moiety (folic acid) into one platform. The average size of these nanoparticles was around 100 nm with low polydispersity. When exposed to clinical doses of 4 Gy X-ray radiation, FA-LPNPs-VP-5-FU generated sufficient amounts of reactive oxygen species, triggering the apoptosis and necrosis pathway of cancer cells. Our combined X-PDT and chemo-drug strategy was effective in inhibiting cancer cells' growth and proliferation. Cell cycle analyses revealed that our treatment induced G2/M and S phase arrest in HCT116 cells. Our results indicate that this combined treatment provides better antitumour effect in colorectal cancer cells than each of these modalities alone. This may offer a novel approach for effective colorectal cancer treatment with reduced off-target effect and drug toxicity.
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Affiliation(s)
- Rui Sang
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, UNSW Sydney, NSW 2052, Australia
| | - Fei Deng
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, UNSW Sydney, NSW 2052, Australia
| | - Alexander Engel
- Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Ewa Goldys
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, UNSW Sydney, NSW 2052, Australia
| | - Wei Deng
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia.
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11
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Deregulation of ribosomal proteins in human cancers. Biosci Rep 2021; 41:230380. [PMID: 34873618 PMCID: PMC8685657 DOI: 10.1042/bsr20211577] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/28/2021] [Accepted: 11/22/2021] [Indexed: 12/26/2022] Open
Abstract
The ribosome, the site for protein synthesis, is composed of ribosomal RNAs (rRNAs) and ribosomal proteins (RPs). The latter have been shown to have many ribosomal and extraribosomal functions. RPs are implicated in a variety of pathological processes, especially tumorigenesis and cell transformation. In this review, we will focus on the recent advances that shed light on the effects of RPs deregulation in different types of cancer and their roles in regulating the tumor cell fate.
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12
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Wu W, Yu N, Li F, Gao P, Lin S, Zhu Y. RPL35 promotes neuroblastoma progression via the enhanced aerobic glycolysis. Am J Cancer Res 2021; 11:5701-5714. [PMID: 34873488 PMCID: PMC8640819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/21/2021] [Indexed: 01/12/2023] Open
Abstract
Neuroblastoma (NB) is an rare type of tumor that almost affects children age 5 or younger due to its rapid proliferation ability. The overall survival rate of patients with advanced NB is not satisfactory. Ribosomal proteins (RPs) play a critical role in the development and progress of cancer. However, the contribution of RPL35 in NB has not been proven. In this study, we reveal that RPL35 is upregulated in NB tissues and the upregulation of RPL35 promotes proliferation and migration of NB while RPL35 knockdown significantly restrained the proliferation of NB cells. In terms of mechanism, glycolysis was decreased and the mitochondrial respiration was increased with knockdown of RPL35 in NB cells, indicating that RPL35 function as a positive regulator in aerobic glycolysis. Importantly, our data indicated that RPL35 deficiency decreased HIF1α expression both in mRNA and protein levels. Western blot analysis showed that RPL35 knockdown has a negative regulatory effect on the ERK pathway, and RPL35 modulated aerobic glycolysis in part through its regulation of the RPL35/ERK/HIF1α axis. Overall, RPL35 functions as a positive regulator of aerobic glycolysis, and the RPL35/ERK/HIF1α axis could be a potential therapeutic target for the therapy of NB.
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Affiliation(s)
- Weidong Wu
- Department of Thoracic Surgery, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China,Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
| | - Nanding Yu
- Department of Thoracic Surgery, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China,Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
| | - Feng Li
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medical and Health Key Laboratory of NeurosurgeryJinan 250014, Shandong, China
| | - Pengqiang Gao
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
| | - Shiyu Lin
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
| | - Yong Zhu
- Department of Thoracic Surgery, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China,Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
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13
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Dai R, Wu M, Zhang Y, Zhu Z, Shi J. G protein nucleolar 3 promotes Non-Hodgkin lymphoma progression by activating the Wnt/β-catenin signaling pathway. Exp Cell Res 2021; 409:112911. [PMID: 34762898 DOI: 10.1016/j.yexcr.2021.112911] [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: 04/19/2021] [Revised: 10/18/2021] [Accepted: 11/06/2021] [Indexed: 10/19/2022]
Abstract
G protein nucleolar 3 (GNL3), which acts as an oncoprotein in various carcinomas, is associated with tumor progression; however, little is known regarding GNL3 function in non-Hodgkin lymphoma (NHL). In this study, we first used in silico analysis to determine associations between GNL3 and diffuse large B-cell lymphoma (DLBCL). We then examined the effect of GNL3 on NHL progression, including cell proliferation, apoptosis, and cell cycle progression, and determined its underlying molecular mechanism using in vitro lymphoma cell lines and in vivo mouse xenograft models. We found that GNL3 mRNA levels were markedly higher in DLBCL tissues than in normal tissues, with these higher levels associated with poor prognosis. Additionally, GNL3 overexpression promoted NHL cell proliferation and cell cycle progression and reduced apoptosis in vitro, and enhanced tumorigenesis in an in vivo xenograft model. Moreover, we found that GNL3 upregulated the levels of Wnt/β-catenin signaling pathway-related factors and downstream target genes, whereas the opposite result was observed in GNL3-silenced cells. Furthermore, a rescue experiment using a Wnt/β-catenin inhibitor (XAV939) confirmed that GNL3 promotes NHL progression by activating the Wnt/β-catenin signaling pathway. These findings demonstrated that GNL3 functions as an oncogenic driver in NHL via the Wnt/β-catenin pathway.
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Affiliation(s)
- Rongqin Dai
- Department of Critical Care Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan province, PR China
| | - Meirong Wu
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian province, PR China
| | - Yin Zhang
- Department of Hematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan province, PR China
| | - Zunmin Zhu
- Department of Hematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan province, PR China.
| | - Jie Shi
- Department of Hematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan province, PR China.
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14
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Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells. Redox Biol 2021; 47:102144. [PMID: 34562873 PMCID: PMC8476449 DOI: 10.1016/j.redox.2021.102144] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/05/2021] [Accepted: 09/19/2021] [Indexed: 12/18/2022] Open
Abstract
Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca2+ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.
Apigenin inhibits the upregulation of TS induced by 5-FU for apoptosis of CRC. FOXM1 silencing enhances the potentiation of apoptosis by apigenin. Suppressing TS and promoting P53 activity by apigenin reduce acquired 5-FU resistance.
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15
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Argenziano M, Arpicco S, Brusa P, Cavalli R, Chirio D, Dosio F, Gallarate M, Peira E, Stella B, Ugazio E. Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research. Pharmaceutics 2021; 13:pharmaceutics13101538. [PMID: 34683830 PMCID: PMC8540327 DOI: 10.3390/pharmaceutics13101538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 01/02/2023] Open
Abstract
Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles to direct drugs towards different receptors that are overexpressed on cancer cells or in the tumor microenvironment. In particular, the review discusses polymeric nanocarriers, liposomes, lipoplexes, niosomes, solid lipid nanoparticles, squalene nanoassemblies and nanobubbles. For each nanocarrier, the main ligands, conjugation strategies and target receptors are described. The literature indicates that polymeric nanoparticles and liposomes stand out as key tools for improving specific drug delivery to the site of action. In addition, solid lipid nanoparticles, squalene nanoparticles and nanobubbles have also been successfully proposed. Taken together, these strategies all offer many platforms for the design of nanocarriers that are suitable for future clinical translation.
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Affiliation(s)
| | - Silvia Arpicco
- Correspondence: (S.A.); (M.G.); Tel.: +39-011-670-6668 (S.A.); +39-011-670-7194 (M.G.)
| | | | | | | | | | - Marina Gallarate
- Correspondence: (S.A.); (M.G.); Tel.: +39-011-670-6668 (S.A.); +39-011-670-7194 (M.G.)
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16
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Thoms HC, Stark LA. The NF-κB Nucleolar Stress Response Pathway. Biomedicines 2021; 9:biomedicines9091082. [PMID: 34572268 PMCID: PMC8471347 DOI: 10.3390/biomedicines9091082] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/09/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.
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17
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Ribosome Biogenesis and Cancer: Overview on Ribosomal Proteins. Int J Mol Sci 2021; 22:ijms22115496. [PMID: 34071057 PMCID: PMC8197113 DOI: 10.3390/ijms22115496] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for protein biosynthesis. Mitochondrial ribosomes (mitoribosomes) perform translation of the proteins essential for the oxidative phosphorylation system. The biogenesis of cytoribosomes and mitoribosomes includes ribosomal RNA processing, modification and binding to ribosomal proteins and is assisted by numerous biogenesis factors. This is a major energy-consuming process in the cell and, therefore, is highly coordinated and sensitive to several cellular stressors. In mitochondria, the regulation of mitoribosome biogenesis is essential for cellular respiration, a process linked to cell growth and proliferation. This review briefly overviews the key stages of cytosolic and mitochondrial ribosome biogenesis; summarizes the main steps of ribosome biogenesis alterations occurring during tumorigenesis, highlighting the changes in the expression level of cytosolic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) in different types of tumors; focuses on the currently available information regarding the extra-ribosomal functions of CRPs and MRPs correlated to cancer; and discusses the role of CRPs and MRPs as biomarkers and/or molecular targets in cancer treatment.
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18
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Saviano F, Lovato T, Russo A, Russo G, Bouton CR, Shattock RJ, Alexander C, Quaglia F, Blakney AK, Gurnani P, Conte C. Ornithine-derived oligomers and dendrimers for in vitro delivery of DNA and ex vivo transfection of skin cells via saRNA. J Mater Chem B 2021; 8:4940-4949. [PMID: 32463058 DOI: 10.1039/d0tb00942c] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gene therapies are undergoing a renaissance, primarily due to their potential for applications in vaccination for infectious diseases and cancers. Although the biology of these technologies is rapidly evolving, delivery strategies need to be improved to overcome the poor pharmacokinetics and cellular transport of nucleic acids whilst maintaining patient safety. In this work, we describe the divergent synthesis of biodegradable cationic dendrimers based on the amino acid ornithine as non-viral gene delivery vectors and evaluate their potential as delivery vectors for DNA and RNA. The dendrimers effectively complexed model nucleic acids at lower N/P ratios than polyethyleneimine and outperformed it in DNA transfection experiments with ratios above 5. Remarkably, all dendrimer polyplexes at N/P = 2 achieved up to 7-fold higher protein content over an optimized PEI formulation when used for transfections with self-amplifying RNA (saRNA). Finally, transfection studies utilizing human skin explants revealed an increase of cells producing protein from 2% with RNA alone to 12% with dendrimer polyplexes, attributed to expression enrichment predominantly in epithelial cells, fibroblasts and leukocytes, with minor enrichment in NK cells, T cells, monocytes, and B cells. Overall, this study indicates the clear potential of ornithine dendrimers as safe and effective delivery vectors for both DNA and RNA therapeutics.
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Affiliation(s)
- Francesca Saviano
- Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
| | - Tatiana Lovato
- Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, NG7 2RD, UK.
| | - Annapina Russo
- Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
| | - Giulia Russo
- Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
| | - Clément R Bouton
- Department of Infectious Disease, Imperial College London, School of Medicine, St Mary's Hospital, Praed Street, London W2 1NY, UK.
| | - Robin J Shattock
- Department of Infectious Disease, Imperial College London, School of Medicine, St Mary's Hospital, Praed Street, London W2 1NY, UK.
| | - Cameron Alexander
- Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, NG7 2RD, UK.
| | - Fabiana Quaglia
- Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
| | - Anna K Blakney
- Department of Infectious Disease, Imperial College London, School of Medicine, St Mary's Hospital, Praed Street, London W2 1NY, UK.
| | - Pratik Gurnani
- Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, NG7 2RD, UK.
| | - Claudia Conte
- Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
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19
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Zhang X, Han J, Feng L, Zhi L, Jiang D, Yu B, Zhang Z, Gao B, Zhang C, Li M, Zhao L, Wang G. DUOX2 promotes the progression of colorectal cancer cells by regulating the AKT pathway and interacting with RPL3. Carcinogenesis 2021; 42:105-117. [PMID: 32531052 PMCID: PMC7877561 DOI: 10.1093/carcin/bgaa056] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/28/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022] Open
Abstract
Dual oxidase 2 (DUOX2) is an important regulatory protein in the organic process of thyroid hormone iodine. Mounting evidence suggests that DUOX2 plays a crucial role in the occurrence and development of cancers. However, the function and mechanism of DUOX2 in colorectal cancer (CRC) have not been fully clarified. In the present study, the relationship between the expression of DUOX2 and the clinicopathological features and prognosis of CRC patients was analyzed. Furthermore, the effects of DUOX2 on proliferation and invasion in vitro and in vivo were examined. DUOX2-associated proteins were identified by immunoprecipitation (IP). Next-generation sequencing detection was performed to illustrate the mechanism of DUOX2 in CRC cells. It was found that the expression levels of DUOX2 in metastatic sites were significantly higher than those in primary tumor tissues, and this was demonstrated to be associated with poor prognosis. The knockdown of DUOX2 inhibited the invasion and migration of CRC cells. Furthermore, DUOX2 regulated the stability of ribosomal protein uL3 (RPL3) by affecting the ubiquitination status of RPL3, and the invasion and migration ability of DUOX2 can be reversed by the overexpression of RPL3. The downregulation of DUOX2 can affect the expression level of a large number of genes, and a number of these are enriched in the PI3K-AKT pathway. Some of the changes caused by DUOX2 can be reversed by RPL3. In summary, DUOX2 exhibits a significantly higher expression in CRC tumor samples, and facilitates the invasion and metastasis ability of CRC cells by interacting with RPL3.
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Affiliation(s)
- Xue Zhang
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Jing Han
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Li Feng
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Lianghui Zhi
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Da Jiang
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Bin Yu
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Zhenya Zhang
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Bo Gao
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Cong Zhang
- Scientific Research Center, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Meng Li
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Lianmei Zhao
- Scientific Research Center, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
| | - Guiying Wang
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, China
- Department of General Surgery, Hebei Medical University Third Affiliated Hospital, Shijiazhuang, Hebei, China
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20
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Pavitra E, Dariya B, Srivani G, Kang SM, Alam A, Sudhir PR, Kamal MA, Raju GSR, Han YK, Lakkakula BVKS, Nagaraju GP, Huh YS. Engineered nanoparticles for imaging and drug delivery in colorectal cancer. Semin Cancer Biol 2021; 69:293-306. [PMID: 31260733 DOI: 10.1016/j.semcancer.2019.06.017] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest diseases worldwide due to a lack of early detection methods and appropriate drug delivery strategies. Conventional imaging techniques cannot accurately distinguish benign from malignant tissue, leading to frequent misdiagnosis or diagnosis at late stages of the disease. Novel screening tools with improved accuracy and diagnostic precision are thus required to reduce the mortality burden of this malignancy. Additionally, current therapeutic strategies, including radio- and chemotherapies carry adverse side effects and are limited by the development of drug resistance. Recent advances in nanotechnology have rendered it an attractive approach for designing novel clinical solutions for CRC. Nanoparticle-based formulations could assist early tumor detection and help to overcome the limitations of conventional therapies including poor aqueous solubility, nonspecific biodistribution and limited bioavailability. In this review, we shed light on various types of nanoparticles used for diagnosis and drug delivery in CRC. In addition, we will explore how these nanoparticles can improve diagnostic accuracy and promote selective drug targeting to tumor sites with increased efficiency and reduced cytotoxicity against healthy colon tissue.
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Affiliation(s)
- Eluri Pavitra
- Department of Biological Engineering, Biohybrid Systems Research Center (BSRC) Inha University, Incheon, 22212, Republic of Korea.
| | - Begum Dariya
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Gowru Srivani
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Sung-Min Kang
- Department of Biological Engineering, Biohybrid Systems Research Center (BSRC) Inha University, Incheon, 22212, Republic of Korea
| | - Afroz Alam
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Putty-Reddy Sudhir
- The Center for Translational Biomedical Research, UNCG, Kannapolis, NC-28081, USA
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW, 2770, Australia; Novel Global Community Educational Foundation, Australia
| | - Ganji Seeta Rama Raju
- Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea
| | - Young-Kyu Han
- Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Yun Suk Huh
- Department of Biological Engineering, Biohybrid Systems Research Center (BSRC) Inha University, Incheon, 22212, Republic of Korea.
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21
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Virgilio A, Esposito V, Pecoraro A, Russo A, Vellecco V, Pepe A, Bucci M, Russo G, Galeone A. Structural properties and anticoagulant/cytotoxic activities of heterochiral enantiomeric thrombin binding aptamer (TBA) derivatives. Nucleic Acids Res 2021; 48:12556-12565. [PMID: 33270863 PMCID: PMC7736819 DOI: 10.1093/nar/gkaa1109] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/09/2020] [Accepted: 11/30/2020] [Indexed: 01/31/2023] Open
Abstract
The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, ‘chair-like’ G-quadruplex structure characteristic of the natural D-TBA. However, although all eight TBA derivatives are endowed with remarkable cytotoxic activities against colon and lung cancer cell lines, only TBA derivatives of the l-series show no anticoagulant activity and are considerably resistant in biological environments.
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Affiliation(s)
- Antonella Virgilio
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Veronica Esposito
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Annalisa Pecoraro
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Annapina Russo
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Valentina Vellecco
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Antonietta Pepe
- Department of Sciences, University of Basilicata, Viale dell'Ateneo Lucano 10, I-85100 Potenza, Italy
| | - Mariarosaria Bucci
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Giulia Russo
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Aldo Galeone
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
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22
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S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells. Int J Mol Sci 2020; 22:ijms22010103. [PMID: 33374288 PMCID: PMC7795960 DOI: 10.3390/ijms22010103] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023] Open
Abstract
Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential in overcoming drug resistance in colon cancer cells devoid of p53. Results: In the present study, we demonstrated that S-adenosyl-l-methionine overcomes uL3-mediated drug resistance in p53 deleted colon cancer cells. In particular, we demonstrated that S-adenosyl-l-methionine causes cell cycle arrest at the S phase; inhibits autophagy; augments reactive oxygen species; and induces apoptosis in these cancer cells. Conclusions: Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes.
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23
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Therapeutic Potential of the Natural Compound S-Adenosylmethionine as a Chemoprotective Synergistic Agent in Breast, and Head and Neck Cancer Treatment: Current Status of Research. Int J Mol Sci 2020; 21:ijms21228547. [PMID: 33202711 PMCID: PMC7697526 DOI: 10.3390/ijms21228547] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022] Open
Abstract
The present review summarizes the most recent studies focusing on the synergistic antitumor effect of the physiological methyl donor S-adenosylmethionine (AdoMet) in association with the main drugs used against breast cancer and head and neck squamous cell carcinoma (HNSCC), two highly aggressive and metastatic malignancies. In these two tumors the chemotherapy approach is recommended as the first choice despite the numerous side effects and recurrence of metastasis, so better tolerated treatments are needed to overcome this problem. In this regard, combination therapy with natural compounds, such as AdoMet, a molecule with pleiotropic effects on multiple cellular processes, is emerging as a suitable strategy to achieve synergistic anticancer efficacy. In this context, the analysis of studies conducted in the literature highlighted AdoMet as one of the most effective and promising chemosensitizing agents to be taken into consideration for inclusion in emerging antitumor therapeutic modalities such as nanotechnologies.
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Pecoraro A, Pagano M, Russo G, Russo A. Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress. Int J Mol Sci 2020; 21:ijms21197334. [PMID: 33020404 PMCID: PMC7582989 DOI: 10.3390/ijms21197334] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/15/2022] Open
Abstract
Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation of stress response pathways plays a central role in cancer initiation and progression, allowing the adaptation of cells to an altered state in the new environment. Autophagy is a tightly regulated pathway which exerts “housekeeping” role in physiological processes. Recently, a growing amount of evidence highlighted the crucial role of autophagy in the regulation of integrated stress responses, including nucleolar and endoplasmic reticulum. In this review, we attempt to afford an overview of the complex role of nucleolar and endoplasmic reticulum stress-response mechanisms in the regulation of autophagy in cancer and cancer treatment.
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Affiliation(s)
| | | | - Giulia Russo
- Correspondence: (G.R.); (A.R.); Tel.: +39-081-678415 (G.R.); +39-081-678414 (A.R.)
| | - Annapina Russo
- Correspondence: (G.R.); (A.R.); Tel.: +39-081-678415 (G.R.); +39-081-678414 (A.R.)
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uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells. Biomolecules 2020; 10:biom10040583. [PMID: 32290083 PMCID: PMC7226491 DOI: 10.3390/biom10040583] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/28/2020] [Accepted: 04/05/2020] [Indexed: 12/29/2022] Open
Abstract
The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers.
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Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells. Int J Mol Sci 2020; 21:ijms21062143. [PMID: 32244996 PMCID: PMC7139652 DOI: 10.3390/ijms21062143] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/05/2020] [Accepted: 03/17/2020] [Indexed: 12/22/2022] Open
Abstract
The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116p53−/− cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.
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Pecoraro A, Carotenuto P, Russo G, Russo A. Ribosomal protein uL3 targets E2F1 and Cyclin D1 in cancer cell response to nucleolar stress. Sci Rep 2019; 9:15431. [PMID: 31659203 PMCID: PMC6817900 DOI: 10.1038/s41598-019-51723-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/01/2019] [Indexed: 12/21/2022] Open
Abstract
Several experimental strategies in the treatment of cancer include drug alteration of cell cycle regulatory pathways as a useful strategy. Extra-ribosomal functions of human ribosomal protein L3 (uL3) may affect DNA repair, cell cycle arrest and apoptosis. In the present study, we demonstrated that uL3 is required for the activation of G1/S transition genes. Luciferase assays established that uL3 negatively regulates the activity of E2F1 promoter. Induced ribosome-free uL3 reduces Cyclin D1 mRNA and protein levels. Using protein/protein immunoprecipitation methods, we demonstrated that uL3 physically interacts with PARP-1 affecting E2F1 transcriptional activity. Our findings led to the identification of a new pathway mediated by uL3 involving E2F1 and Cyclin D1 in the regulation of cell cycle progression.
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Affiliation(s)
- Annalisa Pecoraro
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy
| | - Pietro Carotenuto
- The Institute of Cancer Research, Cancer Therapeutics Unit 15 Cotswold Road, Sutton, London, SM2 5NG, UK
| | - Giulia Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy.
| | - Annapina Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy.
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28
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Su Q, Luo S, Tan Q, Deng J, Zhou S, Peng M, Tao T, Yang X. The role of pyruvate kinase M2 in anticancer therapeutic treatments. Oncol Lett 2019; 18:5663-5672. [PMID: 31788038 PMCID: PMC6865080 DOI: 10.3892/ol.2019.10948] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/06/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer cells are characterized by a high glycolytic rate, which leads to energy regeneration and anabolic metabolism; a consequence of this is the abnormal expression of pyruvate kinase isoenzyme M2 (PKM2). Multiple studies have demonstrated that the expression levels of PKM2 are upregulated in numerous cancer types. Consequently, the mechanism of action of certain anticancer drugs is to downregulate PKM2 expression, indicating the significance of PKM2 in a chemotherapeutic setting. Furthermore, it has previously been highlighted that the downregulation of PKM2 expression, using either inhibitors or short interfering RNA, enhances the anticancer effect exerted by THP treatment on bladder cancer cells, both in vitro and in vivo. The present review summarizes the detailed mechanisms and therapeutic relevance of anticancer drugs that inhibit PKM2 expression. In addition, the relationship between PKM2 expression levels and drug resistance were explored. Finally, future directions, such as the targeting of PKM2 as a strategy to explore novel anticancer agents, were suggested. The current review explored and highlighted the important role of PKM2 in anticancer treatments.
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Affiliation(s)
- Qiongli Su
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Shengping Luo
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Qiuhong Tan
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Jun Deng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
| | - Sichun Zhou
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
| | - Mei Peng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ting Tao
- Department of Pharmacy, Yueyang Maternal-Child Medicine Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
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Carotenuto P, Pecoraro A, Palma G, Russo G, Russo A. Therapeutic Approaches Targeting Nucleolus in Cancer. Cells 2019; 8:E1090. [PMID: 31527430 PMCID: PMC6770360 DOI: 10.3390/cells8091090] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/08/2019] [Accepted: 09/13/2019] [Indexed: 01/08/2023] Open
Abstract
The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging "hallmark" of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.
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Affiliation(s)
- Pietro Carotenuto
- The Institute of Cancer Research, Cancer Therapeutic Unit, London SM2 5NG, UK.
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.
| | - Annalisa Pecoraro
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Gaetano Palma
- Department of Advanced Biomedical Science, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
| | - Giulia Russo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Annapina Russo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
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Soliman NA, Abd-Ellatif RN, ELSaadany AA, Shalaby SM, Bedeer AE. Luteolin and 5-flurouracil act synergistically to induce cellular weapons in experimentally induced Solid Ehrlich Carcinoma: Realistic role of P53; a guardian fights in a cellular battle. Chem Biol Interact 2019; 310:108740. [DOI: 10.1016/j.cbi.2019.108740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/29/2019] [Accepted: 07/05/2019] [Indexed: 12/30/2022]
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31
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Triterpenoids from Cassia fistula L. regulate p53 & ERK2 genes to induce apoptosis in HT-29 colon cancer cells. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2019. [DOI: 10.1016/j.bcab.2019.101286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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32
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Chen J, Stark LA. Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway. Trends Genet 2019; 35:768-780. [PMID: 31434627 DOI: 10.1016/j.tig.2019.07.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/22/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin.
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Affiliation(s)
- Jingyu Chen
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, Scotland EH4 2XU, UK
| | - Lesley A Stark
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, Scotland EH4 2XU, UK.
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33
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Tajmohammadi I, Mohammadian J, Sabzichi M, Mahmuodi S, Ramezani M, Aghajani M, Ramezani F. Identification of Nrf2/STAT3 axis in induction of apoptosis through sub-G 1 cell cycle arrest mechanism in HT-29 colon cancer cells. J Cell Biochem 2019; 120:14035-14043. [PMID: 30993753 DOI: 10.1002/jcb.28678] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/03/2019] [Accepted: 02/14/2019] [Indexed: 01/08/2023]
Abstract
We investigated the role of stattic as an adjuvant molecule to increase the cytotoxicity of 5-fluorouracil (5-FU) through specific inhibition of molecular targets, signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-29 colon cancer cells. Cytotoxicity and apoptotic effects were investigated by methylthiazolyldiphenyl-tetrazolium bromide assay and flow cytometry analysis, respectively. Real-time polymerase chain reaction was applied to assess the messenger RNA (mRNA) level of STAT3, Nrf2, and apoptotic genes including Bax, Bcl-xl, and Bcl-2. The antitumor effect of 5-FU in combination with stattic induced synergistic effect in HT-29 cells with combination indexes (CIs) 0.49. Flow cytometric results related to apoptotic confirmed that there was up to 40% increase in the population of apoptotic cells in HT-29 colon cancer cells incubated with 5-FU and stattic compared with control groups. Our data from gene expression determined a substantial diminish in the mRNA levels of the Nrf2 and antiapoptotic gene Bcl-2 along with a noticeable increase in the level of the proapoptotic Bax in HT-29 colon cells that underwent cotreatment with 5-FU and stattic (P < 0.05). Moreover, the results exhibited that stattic can be used as adjuvant chemotherapy besides the 5-FU. This therapeutic approach in colon cancer could mediate 5-FU chemoresistance via modulating therapeutic targets (ie, STAT3 and Nrf2 pathways) and decreased 5-FU-related adverse effects.
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Affiliation(s)
- Issa Tajmohammadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamal Mohammadian
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Sabzichi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Shiva Mahmuodi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mina Ramezani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marjan Aghajani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
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Chen J, Lobb IT, Morin P, Novo SM, Simpson J, Kennerknecht K, von Kriegsheim A, Batchelor EE, Oakley F, Stark LA. Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway. Nucleic Acids Res 2019; 46:6188-6205. [PMID: 29873780 PMCID: PMC6158704 DOI: 10.1093/nar/gky455] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 05/14/2018] [Indexed: 12/13/2022] Open
Abstract
p53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that artificial disruption of the PolI complex stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of NF-κB and is associated with increased nucleolar size. It is mimicked by CDK4 inhibition and is dependent upon a novel pathway involving UBF/p14ARF and S44 of the protein. We show that blocking TIF-IA degradation blocks stress effects on nucleolar size and NF-κB signalling. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, TIF-IA-NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.
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Affiliation(s)
- Jingyu Chen
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Ian T Lobb
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Pierre Morin
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Sonia M Novo
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - James Simpson
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Kathrin Kennerknecht
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Alex von Kriegsheim
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Emily E Batchelor
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
| | - Fiona Oakley
- Liver Research Group, Institute of Cellular Medicine, 4th Floor, William Leech Building, Framlington Place, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
| | - Lesley A Stark
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, UK
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35
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Zhu H, Zhang C, Guo Z, Yang J, Guo J, Chen C, Yao Q, Liu F, Zhang Q, Gao F. Oridonin induces Mdm2-p60 to promote p53-mediated apoptosis and cell cycle arrest in neuroblastoma. Cancer Med 2019; 8:5313-5326. [PMID: 31339234 PMCID: PMC6718599 DOI: 10.1002/cam4.2393] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/28/2019] [Accepted: 06/16/2019] [Indexed: 12/26/2022] Open
Abstract
Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis‐ and cell cycle arrest‐related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53‐induced Mdm2 (E3 ubiquitin‐protein ligase Mdm2) to generate Mdm2‐p60. The generation of Mdm2‐p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2‐p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.
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Affiliation(s)
- Han‐Qing Zhu
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chao Zhang
- Department of Geriatrics, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhu‐Ying Guo
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jun‐Mei Yang
- Department of Clinical LaboratoryChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Jia‐Hui Guo
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chen Chen
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qiang‐Hua Yao
- Department of PediatricsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Feng Liu
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Quan‐Wu Zhang
- Department of PathologyZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Feng‐Hou Gao
- Department of Oncology, Shanghai 9th People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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36
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Imperatore C, Scuotto M, Valadan M, Rivieccio E, Saide A, Russo A, Altucci C, Menna M, Ramunno A, Mayol L, Russo G, Varra M. Photo-control of cancer cell growth by benzodiazo N-substituted pyrrole derivatives. J Photochem Photobiol A Chem 2019. [DOI: 10.1016/j.jphotochem.2019.03.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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37
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Lin X, Xia Y, Hu D, Mao Q, Yu Z, Zhang H, Li C, Chen G, Liu F, Zhu W, Shi Y, Zhang H, Zheng J, Sun T, Xu J, Chao HH, Zheng X, Luο X. Transcriptome‑wide piRNA profiling in human gastric cancer. Oncol Rep 2019; 41:3089-3099. [PMID: 30896887 PMCID: PMC6448102 DOI: 10.3892/or.2019.7073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 03/08/2019] [Indexed: 12/11/2022] Open
Abstract
Piwi-interacting RNAs (piRNAs) comprise the largest class of non-coding RNAs. They represent a molecular feature shared by all non-aging biological systems, including germline and somatic cancer stem cells, which display an indefinite capacity of renewal and proliferation and are potentially immortal. They have been identified in animal stomachs, but their relationship with human gastric cancers remains largely unclear. The present study aimed to identify the piRNAs associated with human gastric cancers across the whole transcriptome. Fresh tumor tissues and adjacent non-tumorous tissues from stomachs were examined using a piRNA microarray (23,677 piRNAs) that was then validated by qPCR. The differential expression of piRNAs between cases and controls was analyzed. The transposable elements (TEs) that are potentially targeted by the risk piRNAs were searched. The expression of the nearest genes that are complementary to the sequences of the piRNAs was examined in the stomach tissue. The regulatory effects of genome-wide significant and replicated cancer-risk DNA variants on the piRNA expression in stomach were tested. Based on the findings, we identified a total of 8,759 piRNAs in human stomachs. Of all, 50 were significantly (P<0.05) and differentially (>2-fold change) expressed between the cases and controls, and 64.7% of the protein-coding genes potentially regulated by the gastric cancer-associated piRNAs were expressed in the human stomach. The expression of many cancer-associated piRNAs was correlated with the genome-wide and replicated cancer-risk SNPs. In conclusion, we conclude that piRNAs are abundant in human stomachs and may play important roles in the etiological processes of gastric cancers.
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Affiliation(s)
- Xiandong Lin
- Laboratory of Radiation Oncology and Radiobiology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Yan Xia
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Dan Hu
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Qiao Mao
- People's Hospital of Deyang City, Deyang, Sichun 618000, P.R. China
| | - Zongyang Yu
- Department of Medical Oncology, Fuzhou General Hospital of PLA, Fuzhou, Fujian 350025, P.R. China
| | - Hejun Zhang
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Chao Li
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian 350014, P.R. China
| | - Gang Chen
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Fen Liu
- Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350002, P.R. China
| | - Weifeng Zhu
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Yi Shi
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Huihao Zhang
- The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Jianming Zheng
- Huashan Hospital, Fudan University School of Medicine, Shanghai 200040, P.R. China
| | - Tao Sun
- Huashan Hospital, Fudan University School of Medicine, Shanghai 200040, P.R. China
| | - Jianying Xu
- Zhuhai Municipal Maternal and Children's Health Hospital, Zhuhai, Guangdong 519000, P.R. China
| | - Herta H Chao
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, P.R. China
| | - Xiongwei Zheng
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian 350014, P.R. China
| | - Xingguang Luο
- Huilongguan Hospital, Beijing University School of Clinical Medicine, Beijing 100096, P.R. China
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Sun L, Wei L, Wei L, Li D. Correlation between Bax gene polymorphisms and esophagus cancer. Oncol Lett 2018; 16:7097-7101. [PMID: 30546444 PMCID: PMC6256320 DOI: 10.3892/ol.2018.9511] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 09/03/2018] [Indexed: 12/22/2022] Open
Abstract
The present study investigated the association between the G(-248)A single nucleotide polymorphism (SNP) in the promoter region of B-cell lymphoma 2 (Bcl-2) associated X protein (Bax), which is a pro-apoptosis gene and the clinicopathological parameters and prognosis of patients with esophagus cancer. Three genotypes (AA, AG and GG) of Bax G(-248)A SNP were detected in 75 patients with esophageal squamous cell carcinoma (ESCC) via polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). The expression of Bax in tumor tissues from 75 patients with ESCC and 30 para-carcinoma normal tissues were detected via immunohistochemistry. The association between the Bax protein expression and the Bax gene polymorphism was analyzed via the χ2 test. The clinical data of patients was collected and the association between Bax gene polymorphism and the pathological parameters and the prognosis of patients with ESCC was analyzed. The PCR-RFLP results revealed that the number of cases and the distribution frequencies of GG, AG and AA genotypes of Bax polymorphism in patients with ESCC were 50 (66.67%), 16 (21.33%) and 9 (12%), respectively. The immunohistochemical results revealed that the positive expression rate of Bax in ESSC tissues was 42.67%. Bax protein expression was associated with the Bax gene polymorphism, which was associated with outer membrane infiltration, differentiation degree, lymphatic metastasis and the clinical staging of patients. The overall 5-year survival rate of patients was 38.6% (29/75). The survival analyses revealed that the prognosis of patients with AG+AA genotypes was favorable, while that of patients with GG genotype was poor. Bax gene polymorphism was associated with Bax gene expression, tumor staging and lymphatic metastasis in patients with ESCC, which is an influencing factor for the overall survival rate and may be used as a reference index for the prognosis evaluation of patients with ESCC.
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Affiliation(s)
- Lei Sun
- Department of Cardio-Thoracic Surgery, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Lingyun Wei
- Department of Cardio-Thoracic Surgery, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Lei Wei
- Department of Cardio-Thoracic Surgery, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Demin Li
- Department of Cardio-Thoracic Surgery, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
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Kim TJ, Kwon HS, Kang M, Leem HH, Lee KH, Kim DY. The Antitumor Natural Compound Falcarindiol Disrupts Neural Stem Cell Homeostasis by Suppressing Notch Pathway. Int J Mol Sci 2018; 19:ijms19113432. [PMID: 30388862 PMCID: PMC6274977 DOI: 10.3390/ijms19113432] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 10/25/2018] [Accepted: 10/31/2018] [Indexed: 01/01/2023] Open
Abstract
Neural stem cells (NSCs) are undifferentiated, multi-potent cells that can give rise to functional neurons and glial cells. The disruption in NSC homeostasis and/or the impaired neurogenesis lead to diverse neurological diseases, including depression, dementia, and neurodegenerative disorders. Falcarindiol (FAD) is a polyacetylene found in many plants, and FAD shows the cytotoxicity against breast cancers and colon cancers. However, there is no research on the consequence of FAD treatment in normal stem cells. Here, we suggest that FAD has anticancer roles against glioblastoma cells by inducing the differentiation of glioblastoma stem-like cells, as well as activating apoptosis pathway in glioblastoma cells. On the other hand, we also show that FAD has detrimental effects by disrupting the maintenance of normal NSCs and altering the balance between self-renewal and differentiation of NSCs.
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Affiliation(s)
- Tae-Jun Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea.
| | - Hyun-Sook Kwon
- National Development Institute of Korean Medicine, Gyeongsan, Gyeongsangbuk-do 38540, Korea.
| | - Mingyu Kang
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea.
| | - Hyun Hee Leem
- National Development Institute of Korean Medicine, Gyeongsan, Gyeongsangbuk-do 38540, Korea.
| | - Kyung-Ha Lee
- Department of Cosmetic Science and Technology, College of Bio-industry, Daegu Haany University, Gyeongsan 38610, Korea.
| | - Do-Yeon Kim
- Department of Pharmacology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, Daegu 41940, Korea.
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Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis. Cells 2018; 7:cells7100157. [PMID: 30301139 PMCID: PMC6210184 DOI: 10.3390/cells7100157] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/28/2018] [Accepted: 10/03/2018] [Indexed: 12/30/2022] Open
Abstract
Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. While nucleolar and NF-κB pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IκB degradation and NF-κB nuclear translocation. Under these stress conditions, the RelA component of NF-κB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly the discuss how crosstalk between nucleoli and NF-κB signalling may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.
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Clinicopathological and prognostic significance of C/EBP homologous protein (CHOP) in advanced gastric cancer. Pathol Res Pract 2018; 214:1105-1109. [PMID: 29910063 DOI: 10.1016/j.prp.2018.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 06/01/2018] [Accepted: 06/08/2018] [Indexed: 10/14/2022]
Abstract
BACKGROUND Few studies have reported the clinical and prognostic significance of C/EBP homologous protein (CHOP) in advanced gastric cancer (GC). Therefore, the present study investigated the expression of CHOP in advanced GC patients to determine its potential prognostic role. METHODS The levels of CHOP in 95 patients with advanced GC and adjacent non-cancerous tissues were evaluated by qRT-PCR, western blot and immunohistochemistry. Furthermore, the association of CHOP expression with clinicopathological parameters and prognosis of advanced GC patients was analyzed. RESULTS The levels of CHOP were down-regulated in advanced GC compared with non-cancerous tissues (P<0.01). In addition, high CHOP expression more frequently occurred in advanced GC tissues with depth of invasion of T1-2 (P < 0.01), lower clinical stage (TNM Ⅰ-Ⅱ stage) (P<0.05) and without lymph node metastasis (P<0.05). No significant difference was observed between the expression of CHOP and age, gender, tumor size, lesion site and differentiation (P>0.05). The Kaplan-Meier survival analyses showed that the overall survival rate of advanced GC patients with positive CHOP expression was significantly higher than that of patients with negative CHOP expression (P<0.01). Univariate and multivariate Cox proportional hazards models revealed that low CHOP expression (OR = 0.314, 95%CI: 0.176～0.794, P = 0.003) was an independent factor for poor overall survival in advanced GC patients. CONCLUSION Low expression of CHOP predicts the poor prognosis of advanced GC patients, and CHOP may be a prognostic biomarker for patients with advanced GC.
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Srivastava S, Mohammad S, Pant AB, Mishra PR, Pandey G, Gupta S, Farooqui S. Co-delivery of 5-Fluorouracil and Curcumin Nanohybrid Formulations for Improved Chemotherapy Against Oral Squamous Cell Carcinoma. J Maxillofac Oral Surg 2018; 17:597-610. [PMID: 30344406 DOI: 10.1007/s12663-018-1126-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 05/25/2018] [Indexed: 01/10/2023] Open
Abstract
Purpose The chemotherapeutics agent, 5-fluorouracil (5-FU), and curcumin (Cur), a natural antioxidant, has a wide pharmacological window to treat oral carcinoma; however, both drugs have limited bioavailability. This research study designs to develop a nanoemulsions (NEs) formulation by combining 5-FU and Cur to improve anticancer activity against oral cavity squamous cell carcinoma (OSCC) cells from the diversified origin for in vitro analysis, SCC090 (human tongue) and SCC152 (human hypo-pharynx). Methodology NEs formulated through homogenization, applying high-energy ultrasonication technique. The prepared 5-FUNE/Cur-NE/5-FU-Cur-NE were characterized and optimized by different in vitro assays to evaluate release system and treatment of OSCC cells to monitor cellular acceptability, such as in vitro anticancer activity by MTT assay, cell uptake studies and protein expression associated apoptotic study. Results 5-FUNE/Cur-NE/5-FU-Cur-NE successfully formulated and show mean-value of the particle size (150-200 nm), surface charge (- 25.70 to - 37.91 mV), and PDI (0.194). In vitro release of 5-FUNE/Cur-NE/5-FU-Cur-NEs was monitored over a course of 04 days, where acidic pH shows higher release as compared to alkaline pH, along with acceptable stability data. Cytotoxicity study has shown higher-dose-dependent anticancer effect with a reduced IC50 value of NEs as compared to BLNE. Cellular uptake study of 5-FUNE/Cur-NE/5-FU-Cur-NEs upgraded many folds, comparatively BLNE and show potential cell arrest. Additionally, the cell protein (Blc2, Bax, P53, and P21) expression was revised and raised cell apoptosis. Conclusion The combinational loaded, 5-FU and Cur in nanoformulation system have proven their potency to deliver improved anticancer activity, against oral cancer.
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Affiliation(s)
- Saurabh Srivastava
- 1Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, UP India
| | - Shadab Mohammad
- 1Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, UP India
| | - Aditya Bhushan Pant
- 2In Vitro Toxicology Laboratory, CSIR-Indian Institute of Toxicology Research, Lucknow, UP India
| | | | - Gitu Pandey
- 3Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP India
| | - Shalini Gupta
- 4Department of Oral Pathology and Microbiology, King George's Medical University, Lucknow, UP India
| | - Sana Farooqui
- 1Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, UP India
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Jalalian SH, Ramezani M, Abnous K, Taghdisi SM. Targeted co-delivery of epirubicin and NAS-24 aptamer to cancer cells using selenium nanoparticles for enhancing tumor response in vitro and in vivo. Cancer Lett 2017; 416:87-93. [PMID: 29253524 DOI: 10.1016/j.canlet.2017.12.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/14/2017] [Accepted: 12/14/2017] [Indexed: 12/15/2022]
Abstract
Chemotherapy is a commonly used cancer treatment strategy that causes severe side effects by damaging normal tissue. Therefore, targeted drug delivery systems have attracted great attention for the treatment of cancer in recent years. In this study, epirubicin (EPI)-loaded-NAS-24-functionalized PEI-PEG-5TR1 aptamer coated selenium nanoparticles (SeNPs), known as the ENPPASe complex, were developed and used for targeted delivery of both EPI (anticancer drug) and NAS-24 aptamer (apoptosis induction agent) to MCF7 (human breast carcinoma cell) and C26 (murine colon carcinoma cell) cancer cells using 5TR1 aptamer as the target agent. The ENPPASe complex could significantly reduce the toxicity in non-target cells (HEPG2, hepatocellular carcinoma cell). As with the EPI alone, the ENPPASe complex could significantly reduce cell viability in the target cancer cells (MCF-7 and C26). In addition, the complex significantly reduced the tumor growth in cancer-bearing mice compared to EPI treatment alone.
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Affiliation(s)
- Seyed Hamid Jalalian
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Students Research Committee, Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Academic Center for Education, Culture and Research (ACECR)-Mashhad Branch, Mashhad, Iran
| | - Mohammad Ramezani
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Seyed Mohammad Taghdisi
- Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Russo A, Saide A, Smaldone S, Faraonio R, Russo G. Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells. Int J Mol Sci 2017; 18:ijms18030547. [PMID: 28273808 PMCID: PMC5372563 DOI: 10.3390/ijms18030547] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 02/21/2017] [Accepted: 03/01/2017] [Indexed: 01/23/2023] Open
Abstract
Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this study, we analyzed the role of human ribosomal protein uL3 (formerly rpL3) in multidrug resistance. Our studies revealed that uL3 is a key determinant of multidrug resistance in p53-mutated lung cancer cells by controlling the cell redox status. We established and characterized a multidrug resistant Calu-6 cell line. We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. Chromatin immunoprecipitation experiments and luciferase assays demonstrated that uL3 coordinated the expression of stress-response genes acting as transcriptional repressors of solute carrier family 7 member 11 (xCT) and glutathione S-transferase α1 (GST-α1), independently of Nuclear factor erythroid 2-related factor 2 (Nrf2). Altogether our results describe a new function of uL3 as a regulator of oxidative stress response genes and advance our understanding of the molecular mechanisms underlying multidrug resistance in cancers.
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Affiliation(s)
- Annapina Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Assunta Saide
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Silvia Smaldone
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Raffaella Faraonio
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via Sergio Pansini 5, 80131 Naples, Italy.
| | - Giulia Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
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Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress. Int J Mol Sci 2017; 18:ijms18010140. [PMID: 28085118 PMCID: PMC5297773 DOI: 10.3390/ijms18010140] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/12/2016] [Accepted: 01/05/2017] [Indexed: 12/20/2022] Open
Abstract
The nucleolus is the site of ribosome biogenesis, a complex process that requires the coordinate activity of all three RNA polymerases and hundreds of non-ribosomal factors that participate in the maturation of ribosomal RNA (rRNA) and assembly of small and large subunits. Nevertheless, emerging studies have highlighted the fundamental role of the nucleolus in sensing a variety of cellular stress stimuli that target ribosome biogenesis. This condition is known as nucleolar stress and triggers several response pathways to maintain cell homeostasis, either p53-dependent or p53-independent. The mouse double minute (MDM2)-p53 stress signaling pathways are activated by multiple signals and are among the most important regulators of cellular homeostasis. In this review, we will focus on the role of ribosomal proteins in p53-dependent and p53-independent response to nucleolar stress considering novel identified regulators of these pathways. We describe, in particular, the role of ribosomal protein uL3 (rpL3) in p53-independent nucleolar stress signaling pathways.
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