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Cell Death & Disease Jun 2024The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial...
The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.
Topics: Glioblastoma; Humans; Transforming Growth Factor beta; Animals; Signal Transduction; Disease Progression; Cell Line, Tumor; Integrin alphaV; Mice; Brain Neoplasms; Cell Movement; Mice, Nude; Receptor, Transforming Growth Factor-beta Type I; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic
PubMed: 38942749
DOI: 10.1038/s41419-024-06790-8 -
Molecular Neurobiology Jun 2024Brain-specific angiogenesis inhibitor 1 (BAI1) belongs to the adhesion G-protein-coupled receptors, which exhibit large multi-domain extracellular N termini that mediate...
Brain-specific angiogenesis inhibitor 1 (BAI1) belongs to the adhesion G-protein-coupled receptors, which exhibit large multi-domain extracellular N termini that mediate cell-cell and cell-matrix interactions. To explore the existence of BAI1 isoforms, we queried genomic datasets for markers of active chromatin and new transcript variants in the ADGRB1 (adhesion G-protein-coupled receptor B1) gene. Two major types of mRNAs were identified in human/mouse brain, those with a start codon in exon 2 encoding a full-length protein of a predicted size of 173.5/173.3 kDa and shorter transcripts starting from alternative exons at the intron 17/exon 18 boundary with new or exon 19 start codons, predicting two shorter isoforms of 76.9/76.4 and 70.8/70.5 kDa, respectively. Immunoblots on wild-type and Adgrb1 exon 2-deleted mice, reverse transcription PCR, and promoter-luciferase reporter assay confirmed that the shorter isoforms originate from an alternative promoter in intron 17. The shorter BAI1 isoforms lack most of the N terminus and are very close in structure to the truncated BAI1 isoform generated through GPS processing from the full-length receptor. The cleaved BAI1 isoform has a 19 amino acid extracellular stalk that may serve as a receptor agonist, while the alternative transcripts generate BAI1 isoforms with extracellular N termini of 5 or 60 amino acids. Further studies are warranted to compare the functions of these isoforms and examine the distinct roles they play in different tissues and cell types.
PubMed: 38941066
DOI: 10.1007/s12035-024-04293-3 -
Clinical and Experimental Medicine Jun 2024Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for... (Comparative Study)
Comparative Study
Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.
Topics: Humans; Carcinoma, Hepatocellular; Male; Bevacizumab; Middle Aged; Female; Liver Neoplasms; Retrospective Studies; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Antibodies, Monoclonal, Humanized; Treatment Outcome; Immune Checkpoint Inhibitors; China; Chemoembolization, Therapeutic; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Fluorouracil; Leucovorin
PubMed: 38940944
DOI: 10.1007/s10238-024-01415-y -
Biochemistry Research International 2024Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide... (Review)
Review
Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide synthesis, protein transport, and angiogenesis. The scientific literature sheds light on the ubiquitous functions of KIF11 and its involvement in the onset and progression of different pathologies. This review focuses attention on two main points: (1) the correlation between Eg5 and cancer and (2) the involvement of Eg5 in noncancerous conditions. Regarding the first point, several tumors revealed an overexpression of this kinesin, thus pushing to look for new Eg5 inhibitors for clinical practice. In addition, the evaluation of Eg5 expression represents a crucial step, as its overexpression could predict a poor prognosis for cancer patients. Referring to the second point, in specific pathological conditions, the reduced activity of Eg5 can be one of the causes of pathological onset. This is the case of Alzheimer's disease (AD), in which A and Tau work as Eg5 inhibitors, or in acquired immune deficiency syndrome (AIDS), in which Tat-mediated Eg5 determines the loss of CD T-lymphocytes. Reduced Eg5 activity, due to mutations of KIF11 gene, is also responsible for pathological conditions such as microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (MCLRI) and familial exudative vitreous retinopathy (FEVR). In conclusion, this review highlights the double impact that overexpression or loss of function of Eg5 could have in the onset and progression of different pathological situations. This emphasizes, on one hand, a possible role of Eg5 as a potential biomarker and new target in cancer and, on the other hand, the promotion of Eg5 expression/activity as a new therapeutic strategy in different noncancerous diseases.
PubMed: 38939361
DOI: 10.1155/2024/3649912 -
Lab on a Chip Jun 2024Liver cancer represents a significant global burden in terms of cancer-related mortality, with resistance to anti-angiogenic drugs such as Sorafenib and Lenvatinib...
Liver cancer represents a significant global burden in terms of cancer-related mortality, with resistance to anti-angiogenic drugs such as Sorafenib and Lenvatinib presenting a formidable challenge. Tumor angiogenesis, characterized by the formation of new blood vessels within tumors, plays a pivotal role in cancer progression and metastasis. Tumor endothelial cells, specialized endothelial cells lining tumor blood vessels, exhibit unique phenotypic and functional traits that drive aberrant vessel formation and contribute to therapy resistance. CD105, a cell-surface glycoprotein that is highly expressed on endothelial cells during angiogenesis, including tumor endothelial cells, regulates endothelial cell proliferation, migration, and vessel formation by modulating transforming growth factor-beta (TGF-β) signaling pathways. Elevated CD105 expression on tumor endothelial cells correlates with increased angiogenic activity and poor prognosis in cancer patients. Targeting CD105 with antibodies presents a promising strategy to inhibit tumor angiogenesis and disrupt tumor vasculature, offering potential therapeutic benefits by interfering with the tumor microenvironment and inhibiting its progression. This study investigates tumor angiogenesis through a three-dimensional (3D) microfluidic co-culture system incorporating endothelial cells and hepatocellular carcinoma (HCC) cells. The primary focus is on the role of CD105 expression within the liver tumor microenvironment and its contribution to increased chemoresistance. Additionally, this research examines the influence of CD105 expression on the efficacy of tyrosine kinase inhibitors (TKIs) and its pivotal function in facilitating angiogenesis in liver tumors. The proposed microfluidic chip model investigates liver cancer cell interactions within a microfluidic chip model designed to simulate aspects of liver tumor angiogenesis.
PubMed: 38938178
DOI: 10.1039/d4lc00238e -
Communications Chemistry Jun 2024Serine-arginine (SR) proteins are splicing factors that play essential roles in both constitutive and alternative pre-mRNA splicing. Phosphorylation of their C-terminal...
Serine-arginine (SR) proteins are splicing factors that play essential roles in both constitutive and alternative pre-mRNA splicing. Phosphorylation of their C-terminal RS domains by SR protein kinases (SRPKs) regulates their localization and diverse cellular activities. Dysregulation of phosphorylation has been implicated in many human diseases, including cancers. Here, we report the development of a covalent protein-protein interaction inhibitor, C-DBS, that targets a lysine residue within the SRPK-specific docking groove to block the interaction and phosphorylation of the prototypic SR protein SRSF1. C-DBS exhibits high specificity and conjugation efficiency both in vitro and in cellulo. This self-cell-penetrating inhibitor attenuates the phosphorylation of endogenous SR proteins and subsequently inhibits the angiogenesis, migration, and invasion of cancer cells. These findings provide a new foundation for the development of covalent SRPK inhibitors for combatting diseases such as cancer and viral infections and overcoming the resistance encountered by ATP-competitive inhibitors.
PubMed: 38937565
DOI: 10.1038/s42004-024-01230-2 -
Nature Reviews. Disease Primers Jun 2024Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin... (Review)
Review
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
Topics: Multiple Myeloma; Humans; Dexamethasone; Lenalidomide; Antibodies, Monoclonal; Hematopoietic Stem Cell Transplantation; Melphalan; Thalidomide; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38937492
DOI: 10.1038/s41572-024-00529-7 -
BMJ Case Reports Jun 2024Choroidal neovascular membrane (CNVM) in Vogt-Koyanagi-Harada disease (VKH) is a known entity, observed primarily during the chronic convalescent and chronic-recurrent...
Choroidal neovascular membrane (CNVM) in Vogt-Koyanagi-Harada disease (VKH) is a known entity, observed primarily during the chronic convalescent and chronic-recurrent phases of the disease. However, the peripapillary location of CNVM is a rare finding.We describe a case of chronic VKH with bilateral peripapillary CNVM detected using multimodal imaging and the associated differential diagnoses and treatment approach.A combination of anti-vascular endothelial growth factor injections, systemic steroids and immunosuppressants is often required to manage the aggressive course of this choroidal neovascularisation.
Topics: Humans; Uveomeningoencephalitic Syndrome; Choroidal Neovascularization; Tomography, Optical Coherence; Fluorescein Angiography; Diagnosis, Differential; Male; Female; Adult; Angiogenesis Inhibitors
PubMed: 38937264
DOI: 10.1136/bcr-2023-256973 -
Life Sciences Jun 2024Membrane trafficking within the Golgi apparatus plays a pivotal role in the intracellular transportation of lipids and proteins. Dysregulation of this process can give... (Review)
Review
Membrane trafficking within the Golgi apparatus plays a pivotal role in the intracellular transportation of lipids and proteins. Dysregulation of this process can give rise to various pathological manifestations, including cancer. Exploiting Golgi defects, cancer cells capitalise on aberrant membrane trafficking to facilitate signal transduction, proliferation, invasion, immune modulation, angiogenesis, and metastasis. Despite the identification of several molecular signalling pathways associated with Golgi abnormalities, there remains a lack of approved drugs specifically targeting cancer cells through the manipulation of the Golgi apparatus. In the initial section of this comprehensive review, the focus is directed towards delineating the abnormal Golgi genes and proteins implicated in carcinogenesis. Subsequently, a thorough examination is conducted on the impact of these variations on Golgi function, encompassing aspects such as vesicular trafficking, glycosylation, autophagy, oxidative mechanisms, and pH alterations. Lastly, the review provides a current update on promising Golgi apparatus-targeted inhibitors undergoing preclinical and/or clinical trials, offering insights into their potential as therapeutic interventions. Significantly more effort is required to advance these potential inhibitors to benefit patients in clinical settings.
PubMed: 38936604
DOI: 10.1016/j.lfs.2024.122868 -
PloS One 2024Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account....
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
Topics: Animals; Aniline Compounds; Acrylamides; Afatinib; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mice; Humans; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Xenograft Model Antitumor Assays; ErbB Receptors; Quinazolines; Piperazines; Female; Indoles; Pyrimidines
PubMed: 38935790
DOI: 10.1371/journal.pone.0304914