Ghrelin ameliorates cancer cachexia associated with the development of lung adenocarcinoma in mice

Abstract

Cancer cachexia is a multifactorial, critical illness syndrome characterized by an ongoing loss of skeletal muscle and adipose tissue. The reductions in body weight and skeletal muscle mass are important prognostic indicators for cancer patients. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, stimulates food intake and growth hormone secretion, suppresses inflammation, and prevents muscle catabolism. We investigated the pharmacological potential of ghrelin in the treatment of cancer cachexia by using urethane-treated, bronchioalveolar epithelium-specific Pten-deficient mice that developed lung adenocarcinomas. Ghrelin or phosphate-buffered saline was given to mice daily for four weeks beginning at five months after urethane injection, which corresponded to the time point of lung adenocarcinoma formation. Ghrelin inhibited the inductions of C-reactive protein, TNF-α, IL-1β, and IL-6, mitigated the reduction of food intake and fat mass, and consequently ameliorated body weight loss in the mouse model of lung adenocarcinoma. We also demonstrated that skeletal muscle mass and muscle contraction force were retained in ghrelin-treated mice in conjunction with an upregulation of local IGF-1/Akt signaling. Additionally, ghrelin administration reduced the expressions of p-p38 MAPK, p-NFκB, and muscle-specific E3 ubiquitin ligase in the lysates of skeletal muscle in the tumor-bearing state. Our results indicated the efficacy of ghrelin administration in a rodent model of cancer cachexia. The pleiotropic effects of ghrelin against cancer cachexia shown in this study may provide relief from the difficult pathological conditions in patients with cancer cachexia.