AMPK: a key regulator of energy stress and calcium-induced autophagy.

Autophagy is a well-known cell-survival strategy orchestrated by a conserved set of proteins. It equips the cells with mechanisms to attain homeostasis during unfavorable conditions such as stress by breaking down the cellular components and reusing them for energy as well as for building new components required for survival. A basal level of autophagy is required for achieving homeostasis under normal conditions through regular turnover of macromolecules and organelles. Initiation of autophagy is regulated by two key components of the nutrient/energy sensor pathways; mammalian target of rapamycin 1 (mTORC1) and AMP-activated kinase (AMPK). Under energy-deprived conditions, AMPK is activated triggering autophagy, whereas, in nutrient-rich conditions, the growth-promoting kinase mTORC1 is activated inhibiting autophagy. Thus, the reciprocal regulation of autophagy by AMPK and mTORC1 defines a fundamental mechanism by which cells respond to nutrient availability. Interestingly, cytoplasmic calcium is also found to be an activator of AMPK and autophagy through a calmodulin/CaMKKß pathway. However, the physiological significance of the regulation of autophagy by cytoplasmic calcium is currently unclear. This review focuses on the current understanding of the mechanism of autophagy and its regulation by AMPK.

Ricinus communis L. fruit extract inhibits migration/invasion, induces apoptosis in breast cancer cells and arrests tumor progression in vivo.

Medicinal plant-based therapies can be important for treatment of cancer owing to high efficiency, low cost and minimal side effects. Here, we report the anti-cancer efficacy of Ricinus communis L. fruit extract (RCFE) using estrogen positive MCF-7 and highly aggressive, triple negative MDA-MB-231 breast cancer cells. RCFE induced cytotoxicity in these cells in dose and time-dependent manner. It also demonstrated robust anti-metastatic activity as it significantly inhibited migration, adhesion, invasion and expression of matrix metalloproteinases (MMPs) 2 and 9 in both cell lines. Further, flow cytometry analysis suggested RCFE-mediated induction of apoptosis in these cells. This was supported by attenuation of anti-apoptotic Bcl-2, induction of pro-apoptotic Bax and caspase-7 expressions as well as PARP cleavage upon RCFE treatment. RCFE (0.5 mg/Kg body weight) treatment led to significant reduction in tumor volume in 4T1 syngeneic mouse model. HPLC and ESI-MS analysis of active ethyl acetate fraction of RCFE detected four compounds, Ricinine, p-Coumaric acid, Epigallocatechin and Ricinoleic acid. Individually these compounds showed cytotoxic and migration-inhibitory activities. Overall, this study for the first time demonstrates the anti-cancer efficacy of the fruit extract of common castor plant which can be proposed as a potent candidate for the treatment of breast cancer.