Increased hyaluronan deposition (HA) in various cancer tissues, including sarcomas, correlates with disease progression. The receptor for hyaluronic acid-mediated motility (RHAMM) expression is elevated in most human cancers. β-catenin is a critical downstream mediator of the Wnt signaling pathways, facilitating carcinogenic events characterized by deregulated cell proliferation. We previously showed that low molecular weight (LMW) HA/RHAMM/β-catenin signaling axis increases HT1080 fibrosarcoma cell growth. Here, focusing on mechanistic aspects and utilizing immunofluorescence and immunoprecipitation, we demonstrate that LMW HA treatment enhanced RHAMM intracellular localization (p ≤ 0.001) and RHAMM/β-catenin colocalization in HT1080 fibrosarcoma cells (p ≤ 0.05). Downregulating endogenous HA attenuated the association of RHAMM/β-catenin in HT1080 fibrosarcoma cells (p ≤ 0.0.01). Notably, Axin-2, the key β-catenin degradation complex component, and RHAMM were demonstrated to form a complex primarily to cell membranes, enhanced by LMW HA (p ≤ 0.01). In contrast, LMW HA attenuated the association of β-catenin and Axin-2 (p ≤ 0.05). The utilization of FH535, a Wnt signaling inhibitor, showed that LMW HA partially rescued the Wnt-dependent growth of HT1080 cells and restored the expression of Wnt/β-catenin mediators, cyclin-D1 and c-myc (p ≤ 0.05). B6FS fibrosarcoma cells with different HA metabolism do not respond to the LMW HA growth stimulus (p = NS). The present study identifies a novel LMW HA/RHAMM mechanism in a fibrosarcoma model. LMW HA regulates intracellular RHAMM expression, which acts as a scaffold protein binding β-catenin and Axin-2 at different cellular compartments to increase β-catenin expression, transcriptional activity, and fibrosarcoma growth.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s11033-023-08763-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Elevated-c-MYC-expressing Fibrosarcoma Cells With Acquired Gemcitabine Resistance Remain Sensitive to Recombinant Methioninase: A Potential Clinical Strategy for a Recalcitrant Disease.
Cancer Diagn Progn
January 2025
AntiCancer Inc., San Diego, CA, U.S.A.
Background/aim: For second-line chemotherapy of soft-tissue sarcoma, gemcitabine is administered in combination with docetaxel. However, more effective treatments are required for advanced soft-tissue sarcoma, where the efficacy is limited. The purpose of the present study was to compare the efficacy of rMETase and gemcitabine against HT1080 human fibrosarcoma cells and Hs27 normal fibroblasts, as well as to identify and effectively treat HT1080 cells that are resistant to gemcitabine associated with elevated c-MYC.
View Article and Find Full Text PDFSynergistic Eradication of Fibrosarcoma With Acquired Ifosfamide Resistance Using Methionine Restriction Combined With Ifosfamide in Nude-mouse Models.
In Vivo
December 2024
AntiCancer Inc., San Diego, CA, U.S.A.;
Background/aim: Ifosfamide is used clinically with doxorubicin as first-line chemotherapy for soft-tissue sarcoma. However, ifosfamide efficacy for soft-tissue sarcoma is limited due to frequent occurence of ifosfamide resistance and thus more effective therapy is needed. The present study aimed to determine the synergy of recombinant methioninase (rMETase) plus ifosfamide against HT1080 human fibrosarcoma cells in vitro.
View Article and Find Full Text PDFThe Combination of Tumor-targeting A1-R Plus the Autophagy-inhibitor Chloroquine Synergistically Eradicates HT1080 Fibrosarcoma Cells and .
In Vivo
December 2024
AntiCancer Inc., San Diego, CA, U.S.A.;
Background/aim: Salmonella typhimurium A1-R (A1-R) targets and inhibits a wide range of cancer types without continuously infecting healthy tissue. Chloroquine, an antimalarial drug, induces apoptosis and inhibits autophagy in cancer cells. The aim of the present study was to determine the synergy of A1-R plus chloroquine on HT1080 human fibrosarcoma cells in vitro and in a nude-mouse model.
View Article and Find Full Text PDFPGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.
BMB Rep
December 2024
Department of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan 44610, South Korea; Brain Korea 21 Project, University of Ulsan College of Medicine, University of Ulsan, Seoul, South Korea.
A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis.
View Article and Find Full Text PDFFerroptosis and Intrinsic Drug-induced Liver Injury by Acetaminophen and Other Drugs: A Critical Evaluation and Historical Perspective.
J Clin Transl Hepatol
December 2024
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Article Synopsis
- Drug-induced liver injury is a major global health issue, necessitating a better understanding of cell death mechanisms to find new treatments.
- Reactive oxygen species and lipid peroxidation were once key areas of research in liver toxicity but shifted focus to apoptosis, until ferroptosis—a new type of cell death—gained attention due to its unique mechanisms involving glutathione depletion.
- This review examines historical evidence for lipid peroxidation's role in liver damage and how it led to recognizing ferroptosis, highlighting that liver's antioxidant defenses generally prevent significant lipid peroxidation unless severely compromised.
Want 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!