Download Molecular Mechanisms of cancer cachexia: role of cancer

Molecular Mechanisms of cancer cachexia: role of cancer-induced PI3-kinase-gamma in
promoting ghrelin resistance in skeletal muscle
Supervisor: Andrea Graziani, Ph.D., Professor of Biochemistry
Background
Cachexia - Cachexia is an irreversible cancer-associated wasting syndrome, characterized by loss
of muscle mass and body weight. It affects 50-80% of cancer patients, worsening quality of life and
prognosis, and accounting for up to 20% of cancer deaths. As both the knowledge on the
mechanisms underlying cachexia and treatment options are very limited, the understanding of the
molecular mechanisms by which tumor growth causes skeletal muscle wasting is essential to
develop novel therapeutic strategies (Argiles, Nat. Rev. Cancer, 2015).
Ghrelin - Acylated and Unacylated Ghrelin (AG and UnAG) are circulating gastric peptide hormones
generated by fasting-induced ghrelin gene (Muller, Mol. Metabol. 2015). Both AG and UnAG
plasmatic levels are increased in cachectic patients and AG supplemental administration mitigates
cachexia, suggesting that hyper-ghrelinemia is an adaptive response to negative energy balance
occurring in cachexia.
While AG stimulates feeding and Growth Hormone release by binding to its receptor, GHSR1,
UnAG does not bind GHSR. Nevertheless, in skeletal muscle UnAG and AG stimulate anti-atrophic
and mitophagic pathway pathways through binding to a novel receptor yet to be identified.
Activation of c-AMP/PKA and mTORC2-mediated pathways mediates AG and UnAG-induced
protection of skeletal muscle from fasting- and denervation-induced wasting (Porporato, J.
Clin.Invest. 2013; Ruozi, Nature Commun., 2015). In addition UnAG enhances Insulin sensitivity by
stimulating mitophagy and imparing mitochondrial dysfunction (Gortan-Cappellari, Diabetes,
2016) and stimulates self-renewal of satellite cell, the skeletal muscle resident stem cells, thus
promoting their differentiation to multinucleated fibers and enhancing muscle regeneration
(Reano, submitted to ELife, 2016).
Ghrelin resistance – Mounting evidence suggests that cachexia, as well as aging, are associated to
Ghrelin resistance (Fujitsuka, Mol. Psychiatry, 2016). Consistently, we showed that expression of
pro-inflammatory cytokines, namely TNFa/IFNg, is enhanced in cachectic muscle in vivo and that
they induce UnAG resistance in differentiated myotubes in vitro
Hypothesis
This proposal stems from the finding that induction of p101 regulatory subunit of PI3K-gamma in
failing myocardium induces desensitization of beta-adrenergic receptror (AR) and that p101 is
induced in cachectic muscle and by pro-cachectic cytokines (Perino, Mol.Cell, 2011).
Thus, we raised the hypothesis that cachectic muscle may develop resistance to AG/UnAG through
a PI3Kinase-gamma mediated mechanism triggered by cancer-associated inflammation.
Aims and Experimental Strategy
We intend to investigate this hypothesis by:
1) investigating in vitro and in vivo the role of cancer- and chronic inflammation-induced
expression of PI3K-gamma in regulating the skeletal muscle sensitivity/resistance to UnAG in both
differentiated myofibers (activation of mitophagy, Insulin sensitivity and anti-atrophic pathways)
and in satellite cells (self-renewal, myogenic potential)
2) identifying the mechanisms by which inflammation, namely IFNg and TNFa, induces p101 PI3Kgamma expression in skeletal muscle.
3) identifying the receptor mediating AG/UnAG anti-atrophic activity.