Inhibitory effects of c-MYC degrading rLON protease on intestinal polyps in PIRC rat, a familial adenomatous polyposis model.

Authors

Karthikkumar Venkatachalam, Venkateshwar Madka, Gopal Pathuri, Anh Bao, Nicole Stratton, Anil Singh, Mark S Miller, Vignesh Gunasekharan, Chinthalapally V Rao

Published in

Neoplasia (New York, N.Y.). Volume 81. Pages 101360. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, accounting for approximately 10% of all cases, and is the second leading cause of cancer-related deaths in the United States. In patients with Familial Adenomatous Polyposis (FAP), APC mutations drive c-MYC overexpression, promoting metabolic and immune dysregulation that contributes to CRC development, making c-MYC a potential target for FAP-associated chemoprevention. Although no c-MYC inhibitors are currently available, recent evidence indicates that a uropathogenic E. coli protease can degrade c-MYC protein. This study evaluated recombinant LON protease (rLONP) for chemopreventive efficacy in PIRC rats, a model of FAP. Rat pups were genotyped, baseline polyp burden was established by colonoscopy, and animals were randomized to receive saline or rLONP twice daily (2.5 mg/kg, p.o.) for 2 or 4 weeks. Serum analyses showed no significant changes in liver or kidney function markers in rLONP-treated rats compared with controls. rLONP-treated male rats exhibited a ∼40% reduction in colonic polyps at both time points, and small intestinal polyp counts were also lower in treated males and females. Combined analysis demonstrated a ≥60% reduction in total intestinal polyp multiplicity after 2-4 weeks of treatment (p<0.001). Protein expression analyses of colonic polyps revealed decreased c-MYC protein levels following rLONP treatment. Immunohistochemistry further showed reduced Ki-67, Cyclin D1, and c-MYC expression in treated polyps compared with controls. Overall, rLONP was well tolerated and significantly reduced intestinal polyp burden in PIRC rats in this short-term study, supporting further long-term efficacy evaluation.

PMID:
42702203
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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