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A coumarin derivative apaensin was identified to induce apoptosis of cancer cells through its activation of JNK and p38 MAPK, which act coordinately to activate the Nur77-Bcl-2 apoptotic pathway by inducing Nur77 nuclear export and Nur77 interaction with Bcl-2, respectively.Coumarins are plant-derived natural products with a broad range of known pharmacological activities including anticancer effects. However, the molecular mechanisms by which this class of promising compounds exerts their anticancer effects remain largely unknown. We report here that a furanocoumarin named apaensin could effectively induce apoptosis of cancer cells through its activation of Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Apoptosis induction by apaensin in cancer cells was suppressed by chemical inhibitors of JNK and p38 MAPK. Inhibition of the expression of orphan nuclear receptor Nur77 by small interfering RNA (siRNA) approach also abrogated the death effect of apaensin. Molecular analysis demonstrated that JNK activation was required for the nuclear export of Nur77, a known apoptotic event in cancer cells. Although p38 MAPK activation was not involved in Nur77 nuclear export, it was essential for Nur77 mitochondrial targeting through induction of Nur77 interaction with Bcl-2, which is also known to convert Bcl-2 from an antiapoptotic to a proapoptotic molecule. Together, our results identify a new natural product that targets orphan nuclear receptor Nur77 through its unique activation of JNK and p38 MAPK and provide insight into the complex regulation of the Nur77-Bcl-2 apoptotic pathway. [ABSTRACT FROM AUTHOR]