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Identification of early gene expression changes in primary cultured neurons treated with topoisomerase I poisons.

Abstract：

:Topoisomerase 1 (TOP1) poisons like camptothecin (CPT) are currently used in cancer chemotherapy but these compounds can have damaging, off-target effects on neurons leading to cognitive, sensory and motor deficits. To understand the molecular basis for the enhanced sensitivity of neurons to CPT, we examined the effects of compounds that inhibit TOP1-CPT, actinomycin D (ActD) and β-lapachone (β-Lap)-on primary cultured rat motor (MN) and cortical (CN) neurons as well as fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts but transcript levels are reduced in all cell types after treatment with CPT. Microarray analysis was performed to identify differentially regulated transcripts in MNs in response to a brief exposure to CPT. Pathway analysis of the differentially expressed transcripts revealed activation of ERK and JNK signaling cascades in CPT-treated MNs. Immediate-early genes like Fos, Egr-1 and Gadd45b were upregulated in CPT-treated MNs. Fos mRNA levels were elevated in all cell types treated with CPT; Egr-1, Gadd45b and Dyrk3 transcript levels, however, increased in CPT-treated MNs and CNs but decreased in CPT-treated fibroblasts. These transcripts may represent new targets for the development of therapeutic agents that mitigate the off-target effects of chemotherapy on the nervous system.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Rossi SL,Lumpkin CJ,Harris AW,Holbrook J,Gentillon C,McCahan SM,Wang W,Butchbach MER

doi

10.1016/j.bbrc.2016.09.068

subject

Has Abstract

pub_date

2016-10-14 00:00:00

pages

319-324

issue

2

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(16)31528-5

journal_volume

479

pub_type

杂志文章

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