Expression data from APC min/+ mice treated with Lon protease

MYC has been named the quintessential oncogene and is deregulated in the majority of human cancers. Still, finding c-MYC inhibitors for therapeutic use has been problematic and MYC itself has long been viewed as “undruggable”. Here we present a novel strategy for achieving c-MYC inhibition, involving specific bacterial effector molecules. We made the surprising observation that uropathogenic E. coli activate c-MYC degradation and attenuate MYC expression in host cells and tissues. We further identified effector molecules responsible for this effect. The bacterial Lon protease is shown to rapidly degrade c-MYC and therapeutic efficacy is demonstrated in bladder and colon cancer models. Long-term protection, defined by delayed tumor progression, increased survival and low toxicity further supports the therapeutic potential of Lon. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host, which can be exploited to target c-MYC therapeutically in different cancers. C57BL/6J-APCmin/J mice develop spontaneous intestinal adenoma formation, mice were used at either the age of 11 weeks, or 20 weeks. The mice were treated twice daily for 14 days using oral gavage (200 µl) of E. coli 536 WT supernatants (10 µg/kg) or using recombinant Lon Protease (250 µg/ml). At sacrifice, intestines were aseptically harvested for mRNA extraction and analysis. For long-term follow-up experiments, mice were treated per-orally, twice daily for 14 days with Lon protease (250 µg/ml) or received PBS (Sham). Surviving animals were sacrified at week 25. Isolated RNA was subjected to Affymetrix whole genome transcriptomic analysis. For toxicity testing in C57BL/6J WT mice (8 weeks old) were exposed to recombinant Lon protease (rLon) per-orally twice daily for 14 days. Controls received PBS.