0000000000039718
AUTHOR
Javier Alcácer
Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden
Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2'…
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutatio…
Melanoma in the liver: Oxidative stress and the mechanisms of metastatic cell survival.
Abstract Metastatic melanoma is a fatal disease with a rapid systemic dissemination. The most frequent target sites are the liver, bone, and brain. Melanoma metastases represent a heterogeneous cell population, which associates with genomic instability and resistance to therapy. Interaction of melanoma cells with the hepatic sinusoidal endothelium initiates a signaling cascade involving cytokines, growth factors, bioactive lipids, and reactive oxygen and nitrogen species produced by the cancer cell, the endothelium, and also by different immune cells. Endothelial cell-derived NO and H2O2 and the action of immune cells cause the death of most melanoma cells that reach the hepatic microvascul…
Abstract 2810: Pterostilbene, a natural phytoalexin, weakens the antioxidant defenses of aggressive cancer cells in vivo: a pituitary gland- and Nrf2-dependent mechanism
Abstract Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies lack of correlation to the bioavailable concentrations is a critical issue. We studied the underlying mechanisms using different human melanomas (A2058, MeWo and MelJuso) and pancreatic cancers (AsPC-1 and BxPC-3) (with genetic backgrounds correlating with most tumors in patients), growing in nude mice as xenografts, and pterostilbene (Pter, 3’,5’-dimethoxy-4-stilbenol; abundant in e.g. blueberries and a natural dimethoxylated analog of resveratrol). RESULTS: Intravenous administration of Pter decreased human melanoma and pancreatic cancer growth (an effect associated with lower rates of tumor c…
Abstract LB-099: Metabolic vulnerabilities of mesenchymal-like EGFR-mutant NSCLC cells with acquired resistance to tyrosine kinase inhibitors
Abstract Despite the availability of the effective targeted therapies in lung cancer, such as EGFR tyrosine kinase inhibitors (TKIs), drug tolerance and acquired resistance are two common problems that negatively impact lung cancer patient survival. Consequently it is important to understand the molecular basis of the drug tolerance and resistance so that we could formulate effective strategies to ameliorate the efficacy of existing drug and to suppress the emergence of drug resistance. A burgeoning body of literature demonstrated that epigenetic changes by the methylation of DNA and histones are critical in acquired drug resistance, especially in those cancer cells with stem cell-like prop…
Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.
We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in …
Endothelin-1-Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma.
Abstract Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that…
Increased Goodpasture antigen-binding protein expression induces type IV collagen disorganization and deposit of immunoglobulin A in glomerular basement membrane
Increased expression of Goodpasture antigen-binding protein (GPBP), a protein that binds and phosphorylates basement membrane collagen, has been associated with immune complex-mediated pathogenesis. However, recent reports have questioned this biological function and proposed that GPBP serves as a cytosolic ceramide transporter (CERTL). Thus, the role of GPBP in vivo remains unknown. New Zealand White (NZW) mice are considered healthy animals although they convey a genetic predisposition for immune complex-mediated glomerulonephritis. Here we show that NZW mice developed age-dependent lupus-prone autoimmune response and immune complex-mediated glomerulonephritis characterized by elevated GP…
Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro
Background/Objective Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD). The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on prolifer…