Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma.
The nuclear transporter exportin-1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1-selective inhibitors of nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE-induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53-mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT-185 induced apoptosis in MCL cells through p53-dependent and -independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT-185-induced, p53-mediated apoptosis in the MCL cells occurred in a transcription-dependent manner. Exportin-1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT-185 effectively activates p53-mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL.
Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga, Japan.
Mariko
M
Yoshimura
Jo
J
Ishizawa
Vivian
V
Ruvolo
Archana
A
Dilip
Alfonso
A
Quintás-Cardama
Timothy J
TJ
McDonnell
Sattva S
SS
Neelapu
Larry W
LW
Kwak
Sharon
S
Shacham
Michael
M
Kauffman
Yoko
Y
Tabe
Masako
M
Yokoo
Shinya
S
Kimura
Michael
M
Andreeff
Kensuke
K
Kojima
D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
D000179:Acrylates; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C576639:KPT-185; C495901:TP53 protein, human
Apoptosis; KPT-SINE; XPO1; mantle cell lymphoma; p53