Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalisation

Abstract

The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that altered CD44 signalling may be involved in NMR cancer resistance. Although mature ADAM10 is expressed in primary NMR skin fibroblasts, and ionomycin increases cell surface ADAM10 localization, we observed an absence of endogenous CD44 shedding, as well as of exogenous and overexpressed betacellulin, whereas ionomycin induced ADAM10-dependent cleavage of CD44 and betacellulin in mouse primary skin fibroblasts. Overexpressing a hyperactive form of the Ca2+-dependent phospholipid scramblase ANO6 in NMR primary skin fibroblasts increased phosphatidylserine externalization, rescuing the ADAM10 sheddase activity and promoting wound closure. These findings suggest that dysregulation of ADAM10 shedding activity may contribute to the NMR’s cancer resistance.

An interactive cellular ecosystem blocks epithelial transformation in naked mole-rat

“…Naked mole-rat organs resist cancer formation when challenged with carcinogens in vivo 9 , yet how naked mole-rats circumvent malignant transformation is not fully understood. Both cell autonomous and non-autonomous mechanisms have been suggested, including high expression of DNA repair signalling genes 10,11 , heightened sensitivity to contact-inhibition, communication with the extracellular environment [12][13][14][15] , slow somatic mutation rates 16 , and a deficient necroptosis response that dampens immune cell infiltration 9 .…”