Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis

C Wiel,D Gitenay,D F Vincent,D Vindrieux,B Le Calvé,D Bernard,L Bartholin,I Treilleux,V Arfi,H Lallet-Daher,A Augert,E Lelievre,C Reynaud

doi:10.1038/cddis.2013.382

Abstract

Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability.

Highlights

The p16-Rb and p53 pathways are key pathways in the regulation of Oncogene-induced senescence (OIS) and senescence in general,[1,5,6,7,8] but mounting evidence shows that senescence can occur without any involvement of either of these pathways
The cells were immortalized by forced hTert expression and stably infected to express an inducible oncogene: MEK:ER (HEC-TM cells) or, in some experiments, RAF:ER (HEC-TR cells)
In human epithelial cells (HECs)-TM cells, where MEK was activated by a 3-day treatment with 4-hydroxytamoxifen (4-OHT) (Figure 1a), as indicated by increased phosphorylation of its substrate ERK (Figure 1b), we first checked that OIS was induced on d0

Summary

Introduction

The p16-Rb and p53 pathways are key pathways in the regulation of OIS and senescence in general,[1,5,6,7,8] but mounting evidence shows that senescence can occur without any involvement of either of these pathways. LOX-family members are reported to exert both intracellular and extracellular effects, and to share or display specific activities.[19,20,21,22,23] For example, LOX, LOXL1, and LOXL2 share the ability to promote migration, invasion, and metastasis and to regulate extracellular matrix organization.[20,24,25,26,27,28,29,30] How LOX activity affects cancer cell growth is still a matter of debate, as in some cases it is reported to have no effect[24,25] and in other cases to favor cancer cell growth[19,27,28] in vitro or in vivo Both LOXL2 and LOXL3 seem to exert some specific effects on cancer by targeting the embryonic transcription factor Snail,[22] some of the effects shared by LOXL2 and LOX are exerted via activation of the focal-adhesion kinase (FAK).[19,24,27,31,32,33]. We show that LOX activity is a key regulator of OIS, thereby affecting tumorigenesis

Methods

Results

Conclusion