Title: Repurposing of drugs as STAT3 inhibitors for cancer therapy
Authors: Thilakasiri, PS
Dmello, RS
Nero, TL
Parker, MW
Ernst, M
Chand, AL
Issue Year: 2021
Publisher ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Series SEMINARS IN CANCER BIOLOGY:
Abstract Growth differentiating factor-15 (GDF15) is an emerging target for the treatment of obesity and metabolic disease partly due to its ability to suppress food intake. GDF15 expression and secretion are thought to be regulated by a cellular integrated stress response, which involves endoplasmic reticulum (ER) stress. AMPK is another cellular stress sensor, but the relationship between AMPK, ER stress, and GDF15 has not been assessed in vivo. Wildtype (WT), AMPK beta 1 deficient (AMPK beta 1(-/-)), and CHOP-/- mice were treated with three distinct AMPK activators; AICAR, which is converted to ZMP mimicking the effects of AMP on the AMPK gamma isoform, R419, which indirectly activates AMPK through inhibition of mitochondrial respiration, or A769662, a direct AMPK activator which binds the AMPK beta 1 isoform ADaM site causing allosteric activation. Following treatments, liver Gdf15, markers of ER-stress, AMPK activity, adenine nucleotides, circulating GDF15, and food intake were assessed. AICAR and R419 caused ER and energetic stress, increased GDF15 expression and secretion, and suppressed food intake. Direct activation of AMPK beta 1 containing complexes by A769662 increased hepatic Gdf15 expression, circulating GDF15, and suppressed food intake, independent of ER stress. The effects of AICAR, R419, and A769662 on GDF15 were attenuated in AMPK beta 1(-/-) mice. AICAR and A769662 increased GDF15 to a similar extent in WT and CHOP-/- mice. Herein, we provide evidence that AMPK plays a role in mediating the induction of GDF15 under conditions of energetic stress in mouse liver in vivo.
URI: https://publications.svi.edu.au/publications/6941
Other Identifiers 10.1016/j.semcancer.2019.09.022
Publication type Review