Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells

Conventional chemotherapeutic agents and radiation induce accelerated senescence in cancer cells, a phenomenon known as therapy- induced senescence (TIS). Here, we investigated whether TIS can also be induced by targeted inhibition of de novo lipogenesis, which we term fatty acid synthesis therapy-induced senescence (FASTIS). SKBR3 breast cancer cells were treated for 7 days with clinically relevant inhibitors of the key lipogenic enzymes acetyl-CoA carboxylase (ND-646) and fatty acid synthase (TVB-3166) as well as with the well-established, mechanistically distinct TIS inducers bleomycin (an antibiotic that promotes oxidative stress), alisertib (an Aurora A kinase inhibitor that promotes mitotic stress), doxorubicin (a topoisomerase II inhibitor and DNA intercalator that induces DNA damage stress), and palbociclib (a CDK4/6 inhibitor that induces replication stress). To understand the unique versus shared molecular changes of the FASTIS phenotype induced by fatty acid synthesis inhibitors compared to other TIS inducers, we performed mRNA-Seq experiments to provide a comprehensive, high-resolution view of the underlying coding transcriptomes. To account for potential artifacts due to cell subpopulations entering a quiescent state to survive nutrient deprivation after 7 days, parallel mRNA sequencing was also performed in untreated (proliferative) cells at days 0 and 7.