Expression data from mice bladder with MB49-induced cancer 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. Bladder cancer was induced in C57BL/6J female mice by intravesical instillation of MB49 cells. The treatment group received Lon protease (250 µg/ml) or E. coli 536 or PAI I536 bacterial supernatant (approximately 1 hour) by intravesical instillation on days 3, 5, 7, 9 and 11. Sham treated mice received PBS and healthy mice bladders were used as control. Bladder samples were collected after 12 days or 27 days (follow-up). Isolated RNA was subjected to Affymetrix whole genome transcriptomic analysis. For long-term experiments, mice were treated for 12 days with Lon protease (250 µg/ml) followed by twice weekly until day 35. For toxicity testing in C57BL/6J healthy female mice, recombiant Lon protein (250 µg/ml) was instilled intravesically on days 3, 5, 7, 9 and 11 and bladders were collected for RNA isolation after 12 days. Controls received PBS. Isolated RNA was subjected to Affymetrix whole genome transcriptomic analysis.