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Mas Receptor Activation Slows Tumor Growth and Attenuates Muscle Wasting in Cancer

journal contribution
posted on 2024-08-20, 06:25 authored by Kate Murphy, Mohammed I Hossain, Kristy Swiderski, Annabel Chee, Timur Naim, Jennifer Trieu, Vanessa Haynes, Suzannah J Read, David I Stapleton, Sarah M Judge, Jose G Trevino, Andrew R Judge, Gordon S Lynch
Abstract Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. Cachexia robs patients of their strength and capacity to perform daily tasks and live independently. Effective treatments are needed urgently. Here, we investigated the therapeutic potential of activating the “alternative” axis of the renin-angiotensin system, involving ACE2, angiotensin-(1-7), and the mitochondrial assembly receptor (MasR), for treating cancer cachexia. Plasmid overexpression of the MasR or pharmacologic angiotensin-(1-7)/MasR activation did not affect healthy muscle fiber size in vitro or in vivo but attenuated atrophy induced by coculture with cancer cells in vitro. In mice with cancer cachexia, the MasR agonist AVE 0991 slowed tumor development, reduced weight loss, improved locomotor activity, and attenuated muscle wasting, with the majority of these effects dependent on the orexigenic and not antitumor properties of AVE 0991. Proteomic profiling and IHC revealed that mechanisms underlying AVE 0991 effects on skeletal muscle involved miR-23a–regulated preservation of the fast, glycolytic fibers. MasR activation is a novel regulator of muscle phenotype, and AVE 0991 has orexigenic, anticachectic, and antitumorigenic effects, identifying it as a promising adjunct therapy for cancer and other serious muscle wasting conditions. Significance: These findings demonstrate that MasR activation has multiple benefits of being orexigenic, anticachectic, and antitumorigenic, revealing it as a potential adjunct therapy for cancer. See related commentary by Rupert et al., p. 699

History

Journal

Cancer Research

Volume

79

Pagination

706-719

Location

United States

ISSN

0008-5472

eISSN

1538-7445

Language

en

Publication classification

C1.1 Refereed article in a scholarly journal

Issue

4

Publisher

American Association for Cancer Research (AACR)