Rationale: Inducing Cancer differentiation is a promising approach to treat cancer. Here, we identified CHA, a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells.

Methods: cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CHA was evaluated both in vitro and in vivo.

Results: cancer cells treated with CHA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CHA resulted in elevated SUMO1 expression through acting on its 3’UTR and stabilizing the mRNA. The increased SUMO1 caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G0/G1 arrest and maturation phenotype. CHA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naïve mice. In glioma cells, CHA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CHA in glioma cells was comparable to that of temozolomide. CHA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CHA was safe even at very high doses.

Conclusion: CHA might be a safe and effective differentiation-inducer for cancer therapy. “Educating”cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.

The molecular mechanism of the differentiation - inducing effect of chlorogenic acid on cancer cells.

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