Conclusion
Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.
Methods
The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the in vivo therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS).
Results
The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced in vivo delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models.