Therapeutic significance of targeting survivin in cervical cancer and possibility of combination therapy with TRAIL

// Hiroe Nakamura 1, * , Ayumi Taguchi 1, * , Kei Kawana 2 , Satoshi Baba 1 , Akira Kawata 1 , Mitsuyo Yoshida 1 , Asaha Fujimoto 1 , Juri Ogishima 1 , Masakazu Sato 1 , Tomoko Inoue 1 , Haruka Nishida 1 , Hitomi Furuya 1 , Aki Yamashita 1 , Satoko Eguchi 1 , Kensuke Tomio 1 , Mayuyo Mori-Uchino 1 , Katsuyuki Adachi 1 , Takahide Arimoto 1 , Osamu Wada-Hiraike 1 , Katsutoshi Oda 1 , Takeshi Nagamatsu 1 , Yutaka Osuga 1 and Tomoyuki Fujii 1 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan 2 Department of Obstetrics and Gynecology, Nihon University School of Medicine, Itabashiku, Tokyo 173-8610, Japan * Co-first authors Correspondence to: Kei Kawana, email: kkawana-tky@umin.org Keywords: survivin; cervical cancer; TRAIL; human papilloma virus; resveratrol Received: March 10, 2017      Accepted: January 30, 2018      Published: February 05, 2018 ABSTRACT Loss of p53 function due to human papillomavirus (HPV) infection induces resistance to apoptosis in cervical cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a p53-independent manner, may provide an alternative strategy for treating cervical cancer. Survivin, an antiapoptotic protein that is highly expressed in cancer cells, regulates apoptosis and the cell cycle. Here, we investigated the therapeutic potential of targeting survivin, while focusing on the TRAIL-induced apoptosis pathway. The viability and cell cycle of HPV16-positive CaSki and SiHa cells were assessed after survivin knockdown by small interfering RNA (si-survivin). E-cadherin expression was also assessed after si-survivin treatment, using western blotting. SiHa (a TRAIL-resistant cell line) was used for further studies. The small molecule YM155 and resveratrol (RVT; a polyphenol with the potential to suppress survivin expression) were used as survivin inhibitors. The effects of si-survivin and survivin inhibitors on TRAIL- or cisplatin (CDDP)-induced apoptosis were analyzed by annexin-V staining. si-survivin treatment decreased cell viability and led to G2/M arrest, accompanied by morphological changes and E-cadherin upregulation in both CaSki and SiHa cells. si-survivin and YM155 synergistically sensitized TRAIL-resistant SiHa cells to TRAIL-induced apoptosis ( p < 0.05). However, si-survivin and YM155 only slightly increased CDDP-induced apoptosis. RVT markedly enhanced TRAIL-induced apoptosis by suppressing survivin expression. Targeting of survivin expression might be an ideal strategy for cervical cancer treatment as it would decrease viable cell number and enhance apoptosis sensitivity. Further, combination therapy with TRAIL, rather than CDDP, may be compatible with the proposed survivin-targeting strategy.