The variant Senescence-Associated-Secretory-Phenotype induced by centrosome amplification constitutes a pathway that activates Hypoxia-Inducible-Factor-1α

Abstract

ABSTRACTThe Senescence-Associated-Secretory Phenotype (SASP) promote paracrine invasion however may also suppress tumour growth, thus generating complex phenotypic outcomes. Although centrosome amplification can induce proliferation arrest, the subsequent fate of cells with centrosome amplification remains elusive. Here, we report that centrosome amplification induces a variant SASP, constituting a pathway activating paracrine invasion. The centrosome amplification SASP is non-canonical as it lacks detectable DNA damage or prominent NF-κB activation. Instead, involving Rac activation and reactive oxygen species production. Consequently, inducing hypoxia-inducible factor 1α and associated genes, which includes pro-migratory factors such as ANGPTL4. Since senescent cells also have poor fitness, it is tempting to speculate that centrosome amplification induced SASP is one explanation for why extra centrosomes promote malignancy in some experimental models but are neutral or inhibitory in others.