ABSTRACT
The identification of new drugs for the targeted therapy of gastric cancer remains an important need. The RAS/RAF/MEK/ERK/ELK1 signaling cascade is activated in many cancers, including gastric cancer. To identify the targetable inhibitors of the ERK/MAPK pathway, we performed a repurposing screening of a panel of antimicrobial agents in gastric cancer cells using an ERK/MAPK-driven firefly luciferase reporter assay. Multiple antibiotics were identified to inhibit ERK-mediated transcriptional activity. Among them, doxycycline showed high inhibition of ERK/MAPK-regulated transcriptional activity and the levels of ERK proteins. Doxycycline was further identified to inhibit the proliferation and the colony- and spheroid-forming potential of gastric cancer cells. By in vitro signaling pathway and genome-wide expression profiling analyses, doxycycline was identified to inhibit signaling pathways and transcriptional activities regulated by ER, Myc, E2F1, Wnt, SMAD2/3/4, Notch, and OCT4. Doxycycline was also found to activate p53-, ATF6-, NRF1/2-, and MTF1-mediated transcription and inhibit the transcription of histones, proteasomal genes, fibroblast growth factor, and other oncogenic factors. These observations show the multitargeting and targeted therapeutic features of doxycycline for a subset of gastric tumors.
Subject(s)
Adenocarcinoma/drug therapy , Anti-Bacterial Agents/pharmacology , Cell Proliferation/drug effects , Doxycycline/pharmacology , Signal Transduction/drug effects , Stomach Neoplasms/drug therapy , Adenocarcinoma/metabolism , Anti-Bacterial Agents/therapeutic use , Doxycycline/therapeutic use , Drug Screening Assays, Antitumor , Humans , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Stomach Neoplasms/metabolismABSTRACT
Coccinia mosaic Virdhunagar virus (KY860899), Tomato leaf curl New Delhi virus (KY860898) and Tomato leaf curl Virdhunagar alphasatellite (KY848691) were found to be associated with leaf curl disease in Momordica charantia (bitter gourd). The complete nucleotide sequence of Coccinia mosaic Virdhunagar virus showed 82% identity with Coccinia mosaic Tamil Nadu virus (KM244719), whereas Tomato leaf curl New Delhi virus was 96% identical to Tomato leaf curl New Delhi virus (KP868764) and Tomato leaf curl Virdhunagar alphasatellite illustrated 81% similarity with Tomato leaf curl New Delhi alphasatellite (JQ041697). Phylogenetic and RDP analysis revealed the proximity of these begomoviruses with other monopartite begomoviruses and alphasatellites already reported from India. As per the threshold criteria laid down by International Committee on Taxonomy of Viruses for species demarcation in begomoviruses and satellite molecules, the identified virus isolates, Coccinia mosaic Virdhunagar virus and Tomato leaf curl Virdhunagar alphasatellite are proposed as new species. To the best of our knowledge, this is the first ever account of mixed infection of begomoviruses in Momordica charantia, a vegetable crop commonly cultivated throughout India.
