Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer.

ABSTRACT

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.