Oncotarget

Research Papers:

Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis

Asaha Fujimoto _, Kei Kawana, Ayumi Taguchi, Katsuyuki Adachi, Masakazu Sato, Hiroe Nakamura, Juri Ogishima, Mitsuyo Yoshida, Tomoko Inoue, Haruka Nishida, Kensuke Tomio, Aki Yamashita, Yoko Matsumoto, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Takeshi Nagamatsu, Yutaka Osuga and Tomoyuki Fujii

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Oncotarget. 2016; 7:51854-51864. https://doi.org/10.18632/oncotarget.10126

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Abstract

Asaha Fujimoto1, Kei Kawana1, Ayumi Taguchi1, Katsuyuki Adachi1, Masakazu Sato1, Hiroe Nakamura1, Juri Ogishima1, Mitsuyo Yoshida1, Tomoko Inoue1, Haruka Nishida1, Kensuke Tomio1, Aki Yamashita1, Yoko Matsumoto1, Takahide Arimoto1, Osamu Wada-Hiraike1, Katsutoshi Oda1, Takeshi Nagamatsu1, Yutaka Osuga1, Tomoyuki Fujii1

1Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

Correspondence to:

Kei Kawana, email: [email protected]

Keywords: cancer stem-like cell, sphere forming cell, endoplasmic reticulum (ER) stress, cisplatin, tunicamycin

Received: March 13, 2016    Accepted: May 23, 2016    Published: June 17, 2016

ABSTRACT

Although cancer stem cells (CSC) have been implicated in the development of resistance to anti-cancer therapy including chemotherapy, the mechanisms underlying chemo-resistance by CSC have not yet been elucidated. We herein isolated sphere-forming (cancer stem-like) cells from the cervical cancer cell line, SiHa, and examined the unfolded protein reaction (UPR) to chemotherapeutic-induced endoplasmic reticulum (ER) stress. We revealed that tunicamycin-induced ER stress-mediated apoptosis occurred in monolayer, but not sphere-forming cells. Biochemical assays demonstrated that sphere-forming cells were shifted to pro-survival signaling through the inactivation of IRE1 (XBP-1 splicing) and activation of PERK (elF2α phosphorylation) branches under tunicamycin-induced ER stress conditions. The proportion of apoptotic cells among sphere-forming cells was markedly increased by the tunicamycin+PERK inhibitor (PERKi) treatment, indicating that PERKi sensitized sphere-forming cells to tunicamycin-induced apoptosis. Cisplatin is also known to induce ER stress-mediated apoptosis. A low concentration of cisplatin failed to shift sphere-forming cells to apoptosis, although IRE1 branch, but not PERK, was activated. ER stress-mediated apoptosis occurred in sphere-forming cells by the cisplatin+IRE1α inhibitor (IRE1i) treatment. IRE1i, synergistic with cisplatin, up-regulated elF2α phosphorylation, and this was followed by the induction of CHOP in sphere-forming cells. The results of the present study demonstrated that the inhibition of ER stress sensors, combined with ER stress-inducible chemotherapy, shifted cancer stem-like cells to ER stress-mediated apoptosis.


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