STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells
STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells
复制标题
DOI：
10.3892/ijo.2016.3681
复制
发表时间：
2016-11-01
影响因子：
5.2
通讯作者：
Fujii, Tomoyuki
中科院分区：
文献类型：
--
作者：
Nakamura, Hiroe;Taguchi, Ayumi;Fujii, Tomoyuki
在子宫颈癌中，p53诱导的细胞凋亡被人乳头瘤病毒（HPV）衍生的癌蛋白E6废除。尽管肿瘤坏死因子相关凋亡诱导配体（TRAIL）在包括宫颈癌在内的各种癌症中提供肿瘤特异性凋亡，但其敏感性取决于细胞系。信号转导子和转录激活子3（STAT 3）是一种中枢分子，其响应于细胞应激而将细胞命运转变为凋亡或存活。然而，在宫颈癌中STAT 3活性对TRAIL诱导的细胞凋亡的贡献仍然未知。我们使用TRAIL耐药（SiHa）和TRAIL敏感（CaSki）宫颈癌细胞系检测了宫颈癌细胞中TRAIL的敏感性，并专注于涉及凋亡途径的STAT 3功能。在CaSki细胞系中，STAT 3被TRAIL刺激灭活，但在SiHa细胞系中没有。然后，我们使用针对STAT 3的siRNA抑制了SiHa细胞系中的STAT 3表达，并使用STAT 3抑制剂抑制了STAT 3活性;这两种治疗都使SiHa细胞系中TRAIL诱导的凋亡敏化。此外，将SiHa细胞暴露于衣霉素（TM），一种使STAT 3失活的内质网（ER）应激诱导剂，有或没有TRAIL。伴随着STAT 3的失活，TM预处理显著增强TRAIL诱导的细胞凋亡。因此，我们得出结论，TRAIL诱导的细胞凋亡是由STAT 3调节的TRAIL刺激。我们的研究结果还表明，STAT 3抑制增加了恶性肿瘤，特别是HPV相关癌症对基于TRAIL的治疗的敏感性。
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.