Cryptotanshinone, a Potential SIRT3 Inhibitor, Suppresses Colorectal Cancer Proliferation in vitro and in vivo

Cryptotanshinone (CPT) is the main pharmacologically active component of Salvia miltiorrhiza Bunge, and has been demonstrated to have inhibitory effects on a variety of cancer cell types. However, the target(s) of CPT in colorectal cancer (CRC) cells are still to be identified. The aim of this study was to investigate the molecular mechanism of CPT-induced apoptosis in CRC cells. Transcriptome sequencing revealed that 1234 genes were differentially expressed in CPT-treated SW480 cells compared with vehicle control, which were associated with signaling pathways such as PI3K/AKT, Pathways in cancer and biological processes include cell proliferation and mitochondrial function. CCK-8, colony formation assay, and CRC tumor xenograft models suggested that CPT suppressed the colony formation ability and inhibited proliferation of CRC cells in vitro and in vivo, while flow cytometry indicated that CPT arrested the cell cycle in S phase. JC-1, Hoechst and Western blot analysis indicated that CPT promoted apoptosis in CRC cells and triggered alterations in mitochondrial membrane potential. In addition, database analysis showed that high SIRT3 expression in CRC and high SIRT3 expression in CRC was associated with shorter survival times. Immunofluorescence, Western blot, and molecular docking confirmed that CPT was able to target SIRT3 and downregulate SIRT3 protein levels in a concentration-dependent manner. In summary, CPT inhibits SIRT3 protein expression and inhibits CRC proliferation in vitro and in vivo.