CD6 in Human Disease Mikel Gurrea-Rubio, David A. Fox, Javier S. Castresana Cells, 2025 CD6 is a cell surface protein expressed by T cells, a subset of NK cells, a small population of B cells, and thymocytes. CD6 has multiple and complex functions due to its distinct functional epitopes that mediate interactions with several ligands including CD166 (ALCAM) and CD318 (CDCP1). An additional molecule, CD44, is being investigated as a potential new ligand of CD6. CD6 plays critical roles in lymphocyte activation, proliferation, and adhesion to antigen-presenting, epithelial, and cancer cells. CD6 is a risk gene for multiple autoimmune diseases, possibly related to its numerous roles in regulating CD4+T-cell responses. Additionally, CD6 is a potential target for cancer immunotherapy. Here, we dissect the role of CD6 in the pathogenesis of more than 15 diseases and discuss recent data supporting the use of CD6-targeted therapy in humans.
The role of the adenylate kinase 5 gene in various diseases and cancer M. Sarim Siddiqui, Mehdi H. Shahi, Javier S. Castresana Journal of Clinical and Translational Science, 2024 Adenylate kinases (AKs) are important enzymes involved in cellular energy metabolism. Among AKs, AK5 (adenylate kinase 5), a cytosolic protein, is emerging as a significant contributor to various diseases and cellular processes. This comprehensive review integrates findings from various research groups on AK5 since its discovery, shedding light on its multifaceted roles in nucleotide metabolism, energy regulation, and cellular differentiation. We investigate its implications in a spectrum of diseases, including autoimmune encephalitis, epilepsy, neurodegenerative disorders such as Alzheimer’s and Parkinson’s, diabetes, lower extremity arterial disease, celiac disease, and various cancers. Notably, AK5’s expression levels and methylation status have been associated with cancer progression and patient outcomes, indicating its potential as a prognostic indicator. Furthermore, AK5 is implicated in regulating cellular processes in breast cancer, gastric cancer, colorectal carcinoma, prostate cancer, and colon adenocarcinoma, suggesting its relevance across different cancer types. However, a limitation lies in the need for more robust clinical validation and a deeper understanding of AK5’s precise mechanisms in disease pathogenesis, despite its association with various pathophysiological conditions. Nonetheless, AK5 holds promise as a therapeutic target, with emerging evidence suggesting its potential in therapy development.
Exploring the combined anti-cancer effects of sodium butyrate and celastrol in glioblastoma cell lines: a novel therapeutic approach Bahar Kartal, Farika Nur Denizler-Ebiri, Mustafa Güven, Filiz Taşpınar, Hande Canpınar, Sedat Çetin, Tuğçe Karaduman, Serkan Küççüktürk, Javier Castresana, Mehmet Taşpınar Medical Oncology, 2024 Glioblastoma, a highly aggressive and lethal brain cancer, lacks effective treatment options and has a poor prognosis. In our study, we explored the potential anti-cancer effects of sodium butyrate (SB) and celastrol (CEL) in two glioblastoma cell lines. SB, a histone deacetylase inhibitor, and CEL, derived from the tripterygium wilfordii plant, act as mTOR and proteasome inhibitors. Both can cross the blood–brain barrier, and they exhibit chemo- and radiosensitive properties in various cancer models. GB cell lines LN-405 and T98G were treated with SB and CEL. Cell viability was assessed by MTT assay and IC50 values were obtained. Gene expression of DNA repair, apoptosis, and autophagy-related genes was analyzed by RT-PCR. Cell cycle distribution was determined using flow cytometry. Viability assays using MTT assay revealed IC50 values of 26 mM and 22.7 mM for SB and 6.77 μM, and 9.11 μM for CEL in LN-405 and T98G cells, respectively. Furthermore, we examined the expression levels of DNA repair genes (MGMT, MLH-1, MSH-2, MSH-6), apoptosis genes (caspase-3, caspase-8, caspase-9), and an autophagy gene (ATG-6) using real-time polymerase chain reaction. Additionally, flow cytometry analysis revealed alterations in cell cycle distribution following treatment with SB, CEL and their combination. These findings indicate that SB and CEL may act through multiple mechanisms, including DNA repair inhibition, apoptosis induction, and autophagy modulation, to exert their anti-cancer effects in glioblastoma cells. This is the first study providing novel insights into the potential therapeutic effects of SB and CEL in glioblastoma.
Mesenchymal-Stem-Cell-Based Therapy against Gliomas Sisa M. Santillán-Guaján, Mehdi H. Shahi, Javier S. Castresana Cells, 2024 Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
A Comprehensive Review of miRNAs and Their Epigenetic Effects in Glioblastoma Hera Hasan, Mohammad Afzal, Javier S. Castresana, Mehdi H. Shahi Cells, 2023 Glioblastoma is the most aggressive form of brain tumor originating from glial cells with a maximum life expectancy of 14.6 months. Despite the establishment of multiple promising therapies, the clinical outcome of glioblastoma patients is abysmal. Drug resistance has been identified as a major factor contributing to the failure of current multimodal therapy. Epigenetic modification, especially DNA methylation has been identified as a major regulatory mechanism behind glioblastoma progression. In addition, miRNAs, a class of non-coding RNA, have been found to play a role in the regulation as well as in the diagnosis of glioblastoma. The relationship between epigenetics, drug resistance, and glioblastoma progression has been clearly demonstrated. MGMT hypermethylation, leading to a lack of MGMT expression, is associated with a cytotoxic effect of TMZ in GBM, while resistance to TMZ frequently appears in MGMT non-methylated GBM. In this review, we will elaborate on known miRNAs linked to glioblastoma; their distinctive oncogenic or tumor suppressor roles; and how epigenetic modification of miRNAs, particularly via methylation, leads to their upregulation or downregulation in glioblastoma. Moreover, we will try to identify those miRNAs that might be potential regulators of MGMT expression and their role as predictors of tumor response to temozolomide treatment. Although we do not impact clinical data and survival, we open possible experimental approaches to treat GBM, although they should be further validated with clinically oriented studies.
Role of Circular RNA in Brain Tumor Development Swalih P. Ahmed, Javier S. Castresana, Mehdi H. Shahi Cells, 2022 Central nervous system tumors are a leading cause of cancer-related death in children and adults, with medulloblastoma (MB) and glioblastoma (GBM) being the most prevalent malignant brain tumors, respectively. Despite tremendous breakthroughs in neurosurgery, radiation, and chemotherapeutic techniques, cell heterogeneity and various genetic mutations impacting cell cycle control, cell proliferation, apoptosis, and cell invasion result in unwanted resistance to treatment approaches, with a 5-year survival rate of 70–80% for medulloblastoma, and the median survival time for patients with glioblastoma is only 15 months. Developing new medicines and utilizing combination medications may be viewed as excellent techniques for battling MB and GBM. Circular RNAs (circRNAs) can affect cancer-developing processes such as cell proliferation, cell apoptosis, invasion, and chemoresistance in this regard. As a result, several compounds have been introduced as prospective therapeutic targets in the fight against MB and GBM. The current study aims to elucidate the fundamental molecular and cellular mechanisms underlying the pathogenesis of GBM in conjunction with circRNAs. Several mechanisms were examined in detail, including PI3K/Akt/mTOR signaling, Wnt/-catenin signaling, angiogenic processes, and metastatic pathways, in order to provide a comprehensive knowledge of the involvement of circRNAs in the pathophysiology of MB and GBM.
In vitro assessment of the role of p53 on chemotherapy treatments in neuroblastoma cell lines Idoia Blanco-Luquin, Paula Lázcoz, Jon Celay, Javier S. Castresana, Ignacio J. Encío Pharmaceuticals, 2021 Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic drugs and to differentiation agents. Firstly, we characterized 10 neuroblastoma cell lines for alterations at the p53/MDM2/p14ARF signaling pathway by analysis of TP53 point mutations, MYCN and MDM2 amplification, and p14ARF methylation, homozygous deletions, and expression. Secondly, we chose SK-N-FI (mutated at TP53) and SK-N-Be(2) (wild-type TP53) cell lines, treated them with chemotherapeutic agents (doxorubicin, etoposide, cisplatin, and melphalan) and with two isomers of retinoic acid (RA): (9-cis and all-trans). Finally, we analyzed the distribution of the cell cycle, the induction of apoptosis, and the expression levels of p53, p21, and Bcl-2 in those two cell lines. P14ARF did not present promoter methylation, homozygous deletions, and protein expression in any of the 10 neuroblastoma cell lines. One TP53 point mutation was detected in the SK-N-FI cell line. MYCN amplification was frequent, while most cell lines did not present MDM2 amplification. Treatment of SK-N-FI and SK-N-Be(2) cells with doxorubicin, etoposide, cisplatin, and melphalan increased apoptosis and blocked the cycle in G2/M, while retinoic acid isomers induced apoptosis and decreased the percentage of cells in S phase in TP53 mutated SK-N-FI cells, but not in TP53 wild-type SK-N-Be(2) cells. Treatment with cisplatin, melphalan, or 9-cis RA decreased p53 expression levels in SK-N-FI cells but not in SK-N-Be (2). The expression of p21 was not modified in either of the two cell lines. Bcl-2 levels were reduced only in SK-N-FI cells after treatment with cisplatin. However, treatments with doxorubicin, etoposide, or 9-cis-RA did not modify the levels of this protein in either of the two cell lines. In conclusion, TP53 mutated SK-N-FI cells respond better to the retinoic isomers than TP53 wild-type SK-N-Be(2) cells. Although these are in vitro results, it seems that deciphering the molecular alterations of the p53/MDM2/p14ARF signaling pathway prior to treating patients of neuroblastoma might be useful for standardizing therapies with the aim of improving survival.
Molecular study of long-term survivors of glioblastoma by gene-targeted next-generation sequencing Diana Cantero, Ángel Rodríguez de Lope, Raquel Moreno de la Presa, Juan M Sepúlveda, José M Borrás, Javier S Castresana, Nicky D’Haene, Juan F García, Isabelle Salmon, Manuela Mollejo, Juan A Rey, Aurelio Hernández-Laín, Bárbara Meléndez Journal of Neuropathology and Experimental Neurology, 2018
Gene expression analysis of aberrant signaling pathways in meningiomas MIGUEL TORRES-MARTÍN, VICTOR MARTINEZ-GLEZ, CAROLINA PEÑA-GRANERO, ALBERTO ISLA, LUIS LASSALETTA, JOSE M. DE CAMPOS, GIOVANNY R. PINTO, ROMMEL R. BURBANO, BÁRBARA MELÉNDEZ, JAVIER S. CASTRESANA, JUAN A. REY Oncology Letters, 2013
Methylation in malignant astrocytomas María del Mar Inda, Juan A. Rey, Xing Fan, Javier S. Castresana Tumors of the Central Nervous System Astrocytomas Hemangioblastomas and Gangliogliomas, 2012
KIT expression and methylation in medulloblastoma and PNET cell lines and tumors Mónica Enguita-Germán, Mikel Gurrea, Paula Schiapparelli, Thant S. Zhu, Jessica G. Crowley, Lisa L. Hamm, Mark A. Costello, Xiaobing He, Caroline E. Talsma, Callie G. Flack, Shawn L. Hervey-Jumper, Jason A. Heth, Karin M. Muraszko, Juan A. Rey, Xing Fan, Javier S. Castresana Journal of Neuro Oncology, 2011
Suprarenal neuroblastoma with complete transposition of the intrarenal segment of the inferior cava. Report of a case Revista Espanola De Pediatria, 1995
p53 expression in cutaneous malignant melanoma: an immunohistochemical study of 87 cases of primary, recurrent, and metastatic melanoma. Modern Pathology an Official Journal of the United States and Canadian Academy of Pathology Inc, 1994
Oncogene structural changes are unfrequent in malignant bone tumors Acta Orthopaedica Scandinavica Supplement, 1991
A gene near the D3F15S2 site on 3p is expressed in normal human kidney but not or only at a severely reduced level in 11 of 15 primary renal cell carcinomas (RCC) Oncogene, 1990
