Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell-specific apoptosis, making it a prime therapeutic candidate. However, many tumor cells are either innately TRAIL-resistant, or they acquire resistance with adaptive mechanisms that remain poorly understood. In this study, we generated acquired TRAIL resistance models using multiple glioblastoma (GBM) cell lines to assess the molecular alterations in the TRAIL-resistant state. We selected TRAIL-resistant cells through chronic and long-term TRAIL exposure and noted that they showed persistent resistance both in vitro and in vivo. Among known TRAIL-sensitizers, proteosome inhibitor Bortezomib, but not HDAC inhibitor MS-275, was effective in overcoming resistance in all cell models. This was partly achieved through upregulating death receptors and pro-apoptotic proteins, and downregulating major anti-apoptotic members, Bcl-2 and Bcl-xL. We showed that CRISPR/Cas9 mediated silencing of DR5 could block Bortezomib-mediated re-sensitization, demonstrating its critical role. While overexpression of Bcl-2 or Bcl-xL was sufficient to confer resistance to TRAIL-sensitive cells, it failed to override Bortezomib-mediated re-sensitization. With RNA sequencing in multiple paired TRAIL-sensitive and TRAIL-resistant cells, we identified major alterations in inflammatory signaling, particularly in the NF-κB pathway. Inhibiting NF-κB substantially sensitized the most resistant cells to TRAIL, however, the sensitization effect was not as great as what was observed with Bortezomib. Together, our findings provide new models of acquired TRAIL resistance, which will provide essential tools to gain further insight into the heterogeneous therapy responses within GBM tumors. Additionally, these findings emphasize the critical importance of combining proteasome inhibitors and pro-apoptotic ligands to overcome acquired resistance.
Non-small cell lung cancer (NSCLC) is the most pervasive sort of lung cancer with deadly outcome. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify the role of key ferroptosis-related gene (protein kinase AMP-activated catalytic subunit alpha 2, PRKAA2) and explore new directions for the diagnosis and treatment of NSCLC.
Ankylosing spondylitis (AS) is a chronic inflammatory disease involving the spine and bone joints, which is characterized by hyperosteogeny, ossification of ligaments, and ankylosis. Quercetin is a natural polyphenolic compound with various biological activities such as antioxidant, anti-inflammatory, and anti-tumor. It was to explore the effect of quercetin on AS ossification and its molecular mechanism.
Introduction: Low back pain (LBP) is a significant global health burden, with variable treatment outcomes and an unclear underlying molecular mechanism. Effective prediction of treatment responses remains a challenge. In this study, we aimed to develop gene signature-based machine learning models using transcriptomic data from peripheral immune cells to predict treatment outcomes in patients with LBP.
Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China.
A poorer prognosis is thought to be associated with "double expressor lymphomas," which are a subtype of diffuse large B cell lymphomas (DLBCL) that co-express MYC and BCL2. While the role of ubiquitin-specific peptidase 37 (USP37) in lung cancer, where it mediates the deubiquitination and stabilization of c-myc, has been well-documented, its involvement in DLBCL remains unexplored. The use of RT-PCR, immunohistochemistry, or WB test allowed for the detection of elevated USP37 in DLBCL tissues and cells.
Background: Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disorder with a complex etiology. Despite its increasing prevalence, treatment of AD is still limited. Indole-3-carbinol (I3C) is found in cruciferous vegetables and is formed when these vegetables are cut, chewed, or cooked; it exerts diverse pharmacological activities.
