2-Oxonanonoidal Antibiotic Actinolactomycin Inhibits Cancer Progression by Suppressing HIF-1α.
HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.
['Cheng|Jiadong|J|', 'Hu|Lan|L|', 'Yang|Zheng|Z|', 'Suo|Caixia|C|', 'Wang|Yueyang Jack|YJ|', 'Gao|Ping|P|', 'Cui|Chengbin|C|', 'Sun|Linchong|L|']
D000818:Animals D000903:Antibiotics, Antineoplastic D017209:Apoptosis D000068338:Everolimus D005227:Fatty Acids D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D007783:Lactones D008807:Mice, Inbred BALB C D008819:Mice, Nude D009369:Neoplasms D009385:Neoplastic Processes D000078722:PC-3 Cells D015398:Signal Transduction D013302:Streptomyces D058570:TOR Serine-Threonine Kinases
HIF-1α hypoxia inhibitor ALM mTOR combination therapy