AI Article Synopsis
- The DNAJ-PKAc fusion kinase is a characteristic feature of fibrolamellar carcinoma (FLC), a type of liver cancer known for its resistance to traditional chemotherapy treatments.
- Research shows that DNAJ-PKAc can phosphorylate various proteins, including BAG2, which is linked to anti-apoptotic processes and is found in higher levels in FLC tissue samples.
- The study suggests that targeting BAG2 could help overcome chemoresistance, as using the Bcl-2 inhibitor navitoclax increases cancer cell sensitivity to the chemotherapy drug etoposide in cases with DNAJ-PKAc.
Article Abstract
The DNAJ-PKAc fusion kinase is a defining feature of fibrolamellar carcinoma (FLC). FLC tumors are notoriously resistant to standard chemotherapies, with aberrant kinase activity assumed to be a contributing factor. By combining proximity proteomics, biochemical analyses, and live-cell photoactivation microscopy, we demonstrate that DNAJ-PKAc is not constrained by A-kinase anchoring proteins. Consequently, the fusion kinase phosphorylates a unique array of substrates, including proteins involved in translation and the anti-apoptotic factor Bcl-2-associated athanogene 2 (BAG2), a co-chaperone recruited to the fusion kinase through association with Hsp70. Tissue samples from patients with FLC exhibit increased levels of BAG2 in primary and metastatic tumors. Furthermore, drug studies implicate the DNAJ-PKAc/Hsp70/BAG2 axis in potentiating chemotherapeutic resistance. We find that the Bcl-2 inhibitor navitoclax enhances sensitivity to etoposide-induced apoptosis in cells expressing DNAJ-PKAc. Thus, our work indicates BAG2 as a marker for advanced FLC and a chemotherapeutic resistance factor in DNAJ-PKAc signaling scaffolds.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10964278 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2024.113678 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Orthoplastic Approach to the Treatment and Reconstruction of a Neurotrophic Receptor Tyrosine Kinase Type 3 Soft Tissue Sarcoma Arising From the Occipitalis Muscle.
Cureus
November 2024
Medical Oncology, Parkview Health, Fort Wayne, USA.
We present a multidisciplinary approach to the treatment of a neurotrophic receptor tyrosine kinase type 3 (NTRK3) soft tissue sarcoma (STS), arising from the occipitalis muscle. NTRK3 is a mutation only recently described in STS using next-generation sequencing and is rarely implicated in STS.Currently, there is limited literature to guide care.
View Article and Find Full Text PDFEfficacy of Neoadjuvant Therapy for ROS1-Positive Locally-Advanced Lung Adenocarcinoma: A Case Report.
Am J Case Rep
December 2024
Department of Thoracic Surgery, Linyi People's Hospital, Linyi, Shandong, China.
BACKGROUND ROS1 fusion-positive locally-advanced lung adenocarcinoma is a rare malignant tumor with no clear neoadjuvant therapy guidelines and a poor prognosis. This report describes a 49-year-old man with a ROS1 fusion-positive locally-advanced lung adenocarcinoma with a pathological complete response (pCR) to the tyrosine kinase inhibitor crizotinib combined with chemotherapy. CASE REPORT A 49-year-old Chinese man visited the hospital with a cough and phlegm that began over 20 days ago.
View Article and Find Full Text PDFDevelopment of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase.
Nat Commun
December 2024
Institute of Physiological Chemistry, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany.
Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D-binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis.
View Article and Find Full Text PDFIntegrating molecular analyses with the 2021 WHO classification of adult pilocytic astrocytomas.
J Neuropathol Exp Neurol
December 2024
Pathology Department, Complejo Hospitalario Universitario de Toledo, Toledo, Spain.
Pilocytic astrocytomas (PAs) are benign grade 1 gliomas according to the World Health Organization (WHO). They are common in children but rare in adults in whom they may have a worse prognosis. Pediatric PAs are usually associated with dysregulation of the mitogen-activated protein kinase (MAPK) pathway, often involving BRAF alterations such as the KIAA1549::BRAF (K-B) fusion or V600E mutation.
View Article and Find Full Text PDFFusion circRNA F-circEA1 facilitates EML4-ALK1 positive lung adenocarcinoma progression through the miR-4673/SMAD4/ADAR1 axis.
Cell Signal
December 2024
Department of Respiratory Medicine, Jinling Hospital, Nanjing Medical University, Jiangsu Province, China. Electronic address:
Circular RNA (circRNA) can sponge miRNA participate in the tumorigenesis and progression of various cancers. We substantiate for the first time that the fusion circular RNA (F-circRNA) F-circEA1 is involved in driving the echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase variant 1-positive (EML4-ALK1) lung adenocarcinoma (LUAD) progression and the expression of the parental gene EML4-ALK1, molecular mechanisms of F-circEA1 in the EML4-ALK1 LUAD remain unknown. Bioinformatics analysis showed that only miR-4673 can bind to F-circEA1 and bind to EML4-ALK1 3'-UTR to regulate the expression of EML4-ALK1.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!