AMP-activated protein kinase (AMPK) performs a pivotal function in energy 
homeostasis via the monitoring of intracellular energy status. Once activated 
under the various metabolic stress conditions, AMPK regulates a multitude of 
metabolic pathways to balance cellular energy. In addition, AMPK also induces 
cell cycle arrest or apoptosis through several tumor suppressors including LKB1, 
TSC2, and p53. LKB1 is a direct upstream kinase of AMPK, while TSC2 and p53 are 
direct substrates of AMPK. Therefore, it is expected that activators of AMPK 
signal pathway might be useful for treatment or prevention of cancer. In the 
present study, we report that cryptotanshinone, a natural compound isolated from 
Salvia miltiorrhiza, robustly activated AMPK signaling pathway, including LKB1, 
p53, TSC2, thereby leading to suppression of mTORC1 in a number of 
LKB1-expressing cancer cells including HepG2 human hepatoma, but not in 
LKB1-deficient cancer cells. Cryptotanshinone induced HepG2 cell cycle arrest at 
the G1 phase in an AMPK-dependent manner, and a portion of cells underwent 
apoptosis as a result of long-term treatment. It also induced autophagic HepG2 
cell death in an AMPK-dependent manner. Cryptotanshinone significantly 
attenuated tumor growth in an HCT116 cancer xenograft in vivo model, with a 
substantial activation of AMPK signal pathways. Collectively, we demonstrate for 
the first time that cryptotanshinone harbors the therapeutic potential for the 
treatment of cancer through AMPK activation.