Miliusol Suppress Immune Evasion of Colorectal Cancer Through Inhibiting Autophagy

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide and over 1.8 million new patients are diagnosed with this malignancy annually. However, the underlying mechanisms and etiology of colorectal cancer remain elusive. Autophagy is an evolutionarily highly conserved process that degrades and recycling damaged organelles, toxic proteins or misfolded aggregations through engulfing into double-membrane vesicles and finally degraded through lysosome. Increasing evidences suggested that autophagy plays an indispensable role in cancer metastasis and regulating autophagy is becoming a promising strategy for CRC drug discovery.

Miliusol is a natural compound obtained from the medicinal plant Miliusa sinensis[l], It showed potent antitumor effect both in in vitro and in vivo experiments[2]. Whereas the underlying molecular mechanisms of the anticancer effect are urged to be elucidated. Our Western blot results of p62 and LC3I/II level and fluorescence imaging of GFP-RFP-LC3 experiments revealed that miliusol and its analogs can inhibit autophagy flux in time- and dosage-dependent manners. We further checked the expression level of upstream autophagic flux, and found that miliusol specifically reduced the level of Class III PI 3-kinase, which illustrated that miliusol inhibited autophagy through VPS34 complex formation. To proceed further, we will elucidate if miliusol is involving in suppressing the immune evasion through inhibiting autophagy to rescue the normal surface antigen MHC-I level, which may restore surface antigen-presenting to CD8+ T cell and activate immune response correctly. Taken together, we identified miliusol as a novel anticancer lead molecule through inhibiting autophagy and preventing the immune evasion in colorectal cancer, which warrants miliusol and its analogues for further development as anti-colorectal cancer agents.