Inhibition of Cell Proliferation by Euphorbia Factors L1 and L3 from Euphorbia lathyris through the ATF4-CHOP

A luciferase reporter gene assay demonstrates that a methanol extract of the aerial parts of Euphorbia lathyris L. activates reporter gene expression mediated by CCAAT-enhancer-binding protein homologous protein (CHOP) transcriptional activity in the human pancreatic cancer cell line MIA PaCa-2. We isolated 2 lathyrane-type diterpenoids, euphorbia factor L1 (EFL1) and L3 (EFL3), from the extracts. This is the first report of their isolation from aerial parts of this plant. Treatment of the MIA PaCa-2 with EFL1 or EFL3 increased the levels of phosphorylated inositol-requiring enzyme 1 alpha (IRE1α), activating transcription factor 4 (ATF4) and CHOP, involved in the endoplasmic reticulum (ER) stress pathway and cleaved poly (ADP-ribose) polymerase protein (PARP), as apoptotic markers, and inhibited cell proliferation. Thus, EFL1 and EFL3 may be useful in the development of treatments for pancreatic cancer.