Abstract B238: PIN1 (Peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1) is a potential therapeutic target for EBV-associated nasopharyngeal carcinoma.

Abstract

Abstract Nasopharyngeal carcinoma (NPC) is a common EBV-associated human malignancy in Southern China. NPC is highly radiosensitive and radiotherapy is the mainstay treatment for the patients. However, poor clinical outcome remains the major concern in NPC patients with advanced stage disease. Development of new clinical interventions to treat the disease are importance for control this cancer. PIN1 is a highly conserved enzyme that isomerizes specific phosphorylated Ser/Thr-Pro bonds in multiple proteins. It induces conformational changes and modulates functions of many proteins that promote oncogenesis. We have recently confirmed the high PIN1 expression in almost all NPC primary tumours. The aim of this study was to investigate the potential of PIN1 as a therapeutic target for the treatment of NPC. The oncogenic function of PIN1 was investigated in the EBV-positive NPC cell line C666-1 and an immortalized NP epithelial cells NP69. The antitumor effect of PIN1 inhibition was then studied in both in vitro and in vivo NPC models by using the PIN1 inhibitor juglone. In the stable PIN1-expressing NP cells, we found the upregulation of cyclin D1 and activation of MAPL/JNK pathway. Furthermore, we also demonstrated the interaction between PIN1 and EBNA1 in the NPC cells. PIN1 was also shown to interfere the transcription activity of EBNA1 through binding to the phosphorylation sites of EBNA1. Notably, knockdown of PIN1 by siRNA significantly inhibited cell proliferation, DNA synthesis and colony formation of NPC cells. Treatment with juglone demonstrated significant induction of apoptosis and suppression of cyclin D1 expression in C666-1 cells. The IC50 of C666-1 was approximately 6 μM while that of EBV-negative NPC cells HK-1was 10 μM. A dose-dependent inhibition of tumor growth was observed in mice treated with juglone. A significantly growth suppression and cyclin D1 downregulation was found in the tumours of the mice treated with 1-1.5 mg/kg juglone. In conclusion, our findings imply that targeting Pin1 may serve as a potential therapeutic approach for treating patients suffering from this EBV-associated cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B238. Citation Format: Meng Xu, Chit Chow, Chartia Ching Mei Cheung, Grace Tin-Yun Chung, Kwok Wai Lo. PIN1 (Peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1) is a potential therapeutic target for EBV-associated nasopharyngeal carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B238.