STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells.
In cervical cancer, p53-induced apoptosis is abrogated by human papilloma virus (HPV)-derived oncoprotein E6. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) provides tumor-specific apoptosis in various cancers, including cervical cancer, the sensitivity differs depending on the cell lines. Signal transducer and activator of transcription 3 (STAT3) is a hub molecule that shifts the cellular fate to apoptosis or survival in response to cellular stresses. However, the contribution of STAT3 activity to TRAIL-induced apoptosis in cervical cancer remains unknown. We examined the TRAIL sensitivity in cervical cancer cells, using TRAIL-resistant (SiHa) and -sensitive (CaSki) cervical cancer cell lines and focused on STAT3 function involving the apoptotic pathway. STAT3 was inactivated by TRAIL stimulation in the CaSki cell line, but not in the SiHa cell line. We then inhibited STAT3 expression in the SiHa cell line using siRNA against STAT3 and suppressed STAT3 activity using a STAT3 inhibitor; both these treatments sensitized TRAIL-induced apoptosis in the SiHa cell line. Furthermore, the SiHa cells were exposed to tunicamycin (TM), an endoplasmic reticulum (ER) stress inducer that inactivates STAT3, with or without TRAIL. Accompanied by STAT3 inactivation, TM pretreatment significantly enhanced TRAIL-induced apoptosis. We therefore concluded that TRAIL-induced apoptosis was regulated by STAT3 in response to TRAIL stimulation. Our results also suggest that STAT3 inhibition increases the sensitivity of malignancies, particularly HPV-related cancer, to TRAIL-based therapy.
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hiroe
H
Nakamura
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ayumi
A
Taguchi
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kei
K
Kawana
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Akira
A
Kawata
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Mitsuyo
M
Yoshida
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Asaha
A
Fujimoto
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Juri
J
Ogishima
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Masakazu
M
Sato
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Tomoko
T
Inoue
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Haruka
H
Nishida
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hitomi
H
Furuya
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kensuke
K
Tomio
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Satoko
S
Eguchi
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Mayuyo
M
Mori-Uchino
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Aki
A
Yamashita
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Katsuyuki
K
Adachi
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Takahide
T
Arimoto
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Osamu
O
Wada-Hiraike
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Katsutoshi
K
Oda
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Takeshi
T
Nagamatsu
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yutaka
Y
Osuga
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Tomoyuki
T
Fujii
D017209:Apoptosis; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human