Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients.
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.
['Pandian|Jaishree|J|', 'Panneerpandian|Ponmathi|P|', 'Devanandan|Helen Jemimah|HJ|', 'Sekar|Balaji T|BT|', 'Balakrishnan|Karthik|K|', 'Selvarasu|Karthikeyan|K|', 'Muthupandi|Karthikeyan|K|', 'Ganesan|Kumaresan|K|']
D000230:Adenocarcinoma D000900:Anti-Bacterial Agents D049109:Cell Proliferation D004318:Doxycycline D004354:Drug Screening Assays, Antitumor D006801:Humans D020935:MAP Kinase Signaling System D047428:Protein Kinase Inhibitors D015398:Signal Transduction D013274:Stomach Neoplasms
doxycycline gastric cancer targeted therapy ERK/MAPK pathway repurposing