Unacylated ghrelin and AZP531 suppress the 3D growth of breast cancers
CheukMan C Au,
John B Furness,
Kai Ying Soo,
Jason A. Spector,
Lukas E Dow,
Kristy A. Brown
Posted 23 Jan 2020
bioRxiv DOI: 10.1101/2020.01.22.915744
Posted 23 Jan 2020
The gut-derived hormones ghrelin and unacylated ghrelin have been reported to have effects that are independent of binding to the cognate ghrelin receptor, GHSR1a. Little is known of the mechanism of action of ghrelin and unacylated ghrelin at these yet-to-be-identified alternate ghrelin receptors. The present study aimed to characterize effects of unacylated ghrelin on breast cancer cells and explore the therapeutic potential of unacylated ghrelin or cyclic analog AZP531. We report potent effects of unacylated ghrelin, at picomolar doses, on the growth of breast cancer cells, dependent on 3D culture and activation of Gαi. Suppression of MAPK and Akt signaling by unacylated ghrelin leads to cell cycle arrest and apoptosis, and accounts for resistance of cells carrying BRAF or KRAS mutations, or patient-derived breast cancer cells with activated MAPK signaling. AZP531, in clinical trials for Prader-Willi Syndrome, also suppresses the growth of breast cancer cells in vitro and in vivo.
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