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Carcinogenesis Advance Access originally published online on March 26, 2009
Carcinogenesis 2009 30(5):824-831; doi:10.1093/carcin/bgp067
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PLAB induction in fenretinide-induced apoptosis of ovarian cancer cells occurs via a ROS-dependent mechanism involving ER stress and JNK activation

Valentina Appierto, Paola Tiberio, Maria Grazia Villani, Elena Cavadini and Franca Formelli*

Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy

* To whom correspondence should be addressed. Tel: +39 02 2390 2706; Fax: +39 02 2390 2692; Email: franca.formelli{at}istitutotumori.mi.it

Fenretinide [N-(4-hydroxyphenyl)-retinamide (4HPR)] is a synthetic retinoid with antitumor activity that induces apoptosis in various types of cancer cell. We showed previously that 4HPR upregulates the proapoptotic gene placental bone morphogenetic protein (PLAB), which is a mediator of 4HPR-induced apoptosis in ovarian cancer cells. Here, we investigated the signaling cascade involving PLAB that mediates the apoptotic effect. In 4HPR-sensitive ovarian cancer cells, 4HPR-induced reactive oxygen species (ROS) are involved in PLAB upregulation and apoptosis, both events abrogated by the antioxidants vitamin C and butylated hydroxyanisole. We analyzed the expression and activation of endoplasmic reticulum (ER) stress-associated molecules and show that 4HPR-induced ER stress is a consequence of ROS generation. Salubrinal, an ER stress inhibitor, abrogated 4HPR-induced PLAB upregulation and protected the cells from apoptosis. Downstream of ROS generation and ER stress, 4HPR activated c-Jun N-terminal kinase (JNK), which was inhibited by vitamin C and salubrinal. The JNK inhibitor SP600125 reduced 4HPR-induced PLAB upregulation, by decreasing PLAB mRNA half-life, and protected the cells from apoptosis. These data indicate that 4HPR-induced PLAB upregulation occurs downstream of a signaling cascade involving ROS generation, ER stress induction and JNK activation and that these steps are mediators of 4HPR-induced apoptosis.

Abbreviations: ARE, AU-rich element; BHA, butylated hydroxyanisole; BiP, immunoglobulin-binding protein; eIF2{alpha}, alpha-subunit of eukaryotic initiation factor 2; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GRP78, glucose-regulated protein 78KD; HSP, heat shock protein; 4HPR, N-(4-hydroxyphenyl)-retinamide; IC50, inhibiting concentration 50%; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PARP, poly(adenosine diphosphate-ribose)polymerase; PCR, polymerase chain reaction; PLAB, placental bone morphogenetic protein; ROS, reactive oxygen species; XBP-1, X-box binding protein-1

Received November 14, 2008; revised February 23, 2009; accepted March 21, 2009.


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