An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderate levels of KIT expression were detected in ∼85% of SPINK1-positive PCa specimens. We show KIT signaling orchestrates SPINK1-mediated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/ß-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling led to restoration of AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide distinct treatment modalities for advanced-stage SPINK1-positive patients.

Transcription networks rewire gene repertoire to coordinate cellular reprograming in prostate cancer.

Transcription factors (TFs) represent the most commonly deregulated DNA-binding class of proteins associated with multiple human cancers. They can act as transcriptional activators or repressors that rewire the cistrome, resulting in cellular reprogramming during cancer progression. Deregulation of TFs is associated with the onset and maintenance of various cancer types including prostate cancer. An emerging subset of TFs has been implicated in the regulation of multiple cancer hallmarks during tumorigenesis. Here, we discuss the role of key TFs which modulate transcriptional cicuitries involved in the development and progression of prostate cancer. We further highlight the role of TFs associated with key cancer hallmarks, including, chromatin remodeling, genome instability, DNA repair, invasion, and metastasis. We also discuss the pluripotent function of TFs in conferring lineage plasticity, that aids in disease progression to neuroendocrine prostate cancer. At the end, we summarize the current understanding and approaches employed for the therapeutic targeting of TFs and their cofactors in the clinical setups to prevent disease progression.

Inhibition and disruption of amyloid formation by the antibiotic levofloxacin: A new direction for antibiotics in an era of multi-drug resistance.

Neurodegenerative diseases are a group of debilitating maladies involving protein aggregation. To this day, all advances in neurodegenerative disease therapeutics have helped symptomatically but have not prevented the root cause of the disease, i.e., the aggregation of involved proteins. Antibiotics are becoming increasingly obsolete due to the rising multidrug resistance strains of bacteria. Thus, antibiotics, if put to different use as therapeutics against other diseases, could pave a new direction to the world of antibiotics. Hence, we studied the antibiotic levofloxacin for its potential anti-amyloidogenic behavior using human lysozyme, a protein involved in non-systemic amyloidosis, as a model system. At the sub-stoichiometric level, levofloxacin was able to inhibit amyloid formation in human lysozyme as observed by various spectroscopic and microscopic methods, with IC50 values as low as 8.8 ± 0.1 µM. Levofloxacin also displayed a retarding effect on seeding phenomena by elongating the lag-phase (from 0 to 88 h) at lower concentration, and arresting lysozyme fibrillation at the lag stage in sub-stoichiometric concentrations. Structural and computational analyses provided mechanistic insight showing that levofloxacin stabilizes the lysozyme in the native state by binding to the aggregation-prone residues, and thereby inhibiting amyloid fibrillation. Levofloxacin also showed the property of disrupting amyloid fibrils into a smaller polymeric form of proteins which were less cytotoxic as confirmed by hemolytic assay. Therefore, we throw new light on levofloxacin as an amyloid inhibitor and disruptor which could pave way to utilization of levofloxacin as a potential therapeutic against non-systemic amyloidosis and neurodegenerative diseases.