Albert Einstein Cancer Center

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1-dependent

Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. AECC investigators McDaid, Horwitz, and collaborators, developed a  discodermolide-resistant cell line, AD32, from the human lung cancer cell line A549. AD32 cells were shown  to have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide by restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 partially restored drug sensitivity and enhanced proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs identified differentially expressed genes involved in p53 signaling, G2/M checkpoint regulation, and in the BRCA1 response to DNA damage. p53 protein expression was up-regulated with increased nuclear localization in AD32 cells relative to parental A549 cells and the stability of p53 was enhanced in AD32 cells. Based on these findings, the investigators proposed a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence. 

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