ABSTRACT
Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.
Subject(s)
Disease Progression , Hedgehog Proteins , Lymphoma, B-Cell , Procollagen-Proline Dioxygenase , Repressor Proteins , Signal Transduction , Hedgehog Proteins/metabolism , Humans , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Mice , Animals , Repressor Proteins/metabolism , Repressor Proteins/genetics , Procollagen-Proline Dioxygenase/metabolism , Hydroxylation , Paracrine Communication , Cell Proliferation , Kinesins/metabolism , Kinesins/genetics , Cell Line, Tumor , Prolyl HydroxylasesABSTRACT
Bladder cancer (BLCA) remains a difficult malignancy to manage because of its high recurrence, intense follow-up, and invasive diagnostic and treatment techniques. Immune checkpoint inhibitors (ICIs) have forged a new direction for the treatment of BLCA, but it is currently challenging to predict whether an individual patient will be sensitive to ICIs. We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells (BCCs) culturing using our previously reported BCC culture platform. We used flow cytometry (FCM) to measure the expression levels of Programmed Death-Ligand 1 (PD-L1) on BCCs before and after interferon-gamma (IFN-γ) treatment and found that PD-L1 expression and the sensitivities to IFN-γ varied among patients. RNA-sequencing, western blotting, and programmed death-1 (PD-1) binding assays confirmed that the BCC FCM-based PD-L1 detection platform (BC-PD-L1) was reliable and was not hindered by the glycosylation of PD-L1. In the subsequent retrospective study, we found that IFN-γ-stimulated PD-L1 (sPD-L1) expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients. Importantly, the prognostic value was similar or even better in urine-derived BC-PD-L1 (UBC-PD-L1). Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix, cell-cell adhesion, and positive regulation of the immune system. In addition, the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients. In conclusion, as a novel personalized urine-detection method, UBC-PD-L1 may provide a rapid, accurate, and non-invasive tool for monitoring tumor progression, predicting therapeutic responses, and helping improve BLCA clinical treatment in future.
ABSTRACT
Prostate cancer (PCa) is the second most prevalent malignancy in males across the world. A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa. Herein, we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients, including gene mutations, mRNA/protein/surface protein distributions, and pharmaceutical responses. The multi-omics analyses identify Anterior Gradient 2 (AGR2) as a pre-operative prognostic biomarker in PCa. Through the drug library screening, we describe crizotinib as a selective compound for malignant PCa primary cells. We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations. Surprisingly, the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model. Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses, allowing for more precise diagnosis and therapies.
Subject(s)
Multiomics , Prostatic Neoplasms , Male , Humans , Crizotinib/pharmacology , Crizotinib/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Proteins/metabolism , Mucoproteins/therapeutic use , Oncogene Proteins/therapeutic useABSTRACT
Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.