Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer.
Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer.
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DOI：
10.1371/journal.pone.0087900
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Toyooka S
中科院分区：
文献类型：
--
作者：
Shien K;Tanaka N;Watanabe M;Soh J;Sakaguchi M;Matsuo K;Yamamoto H;Furukawa M;Asano H;Tsukuda K;Nasu Y;Huh NH;Miyoshi S;Kumon H;Toyooka S
REIC/Dkk-3在广泛的人类癌细胞中下调，被认为是肿瘤抑制因子。我们先前报道了表达REIC/Dkk-3的腺病毒载体（Ad-REIC）诱导人前列腺癌的内质网（ER）应激和癌症特异性凋亡。在这项研究中，我们研究了Ad-REIC对非小细胞肺癌（NSCLC）的治疗作用。我们检测了Ad-REIC对25种NSCLC细胞株的体外抗肿瘤作用和对A549细胞的体内抗肿瘤作用。这些细胞系中的两个被人工建立为EGFR-酪氨酸激酶抑制剂（TKI）抗性亚系。在感染复数（MOI）为20（20 MOI）时，Ad-REIC处理在25个细胞系中的13个（52%）中抑制了40%或更多的细胞活力。这些细胞系被认为是高度敏感的细胞。非恶性永生化细胞系OUMS-24的细胞活力在200 MOI的Ad-REIC下不受抑制。Ad-REIC对EGFR-TKI耐药亚系的影响与亲代细胞系相当。在这里，我们证明了Ad-REIC处理激活了NSCLC细胞系中的c-Jun N-末端激酶（JNK），表明GRP 78/BiP（GRP 78）上调诱导ER应激并导致细胞凋亡。单次瘤内注射Ad-REIC可显著抑制A549细胞的体内致瘤性生长。作为Ad-REIC治疗NSCLC敏感性的预测因素，我们检测了GRP 78和柯萨奇病毒和腺病毒受体（CAR）的表达状态。我们发现GRP 78和CAR表达状态的组合可以用作NSCLC细胞中Ad-REIC敏感性的预测因子。Ad-REIC诱导NSCLC细胞中JNK活化和随后的凋亡。我们的研究表明，Ad-REIC对NSCLC具有治疗潜力，并且GRP 78和CAR的表达状态可以预测Ad-REIC的潜在治疗益处。
REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC). We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines. Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a non-malignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells. Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
6.4
作者：
BAI, L;MIHARA, K;NAMBA, M
通讯作者：
NAMBA, M
影响因子：
11.5
作者：
Sterman, Daniel H.;Recio, Adri;Albelda, Steven M.
通讯作者：
Albelda, Steven M.
DOI：
10.1006/bbrc.1999.2067
发表时间：
2000-02-05
影响因子：
3.1
作者：
Tsuji, T;Miyazaki, M;Namba, M
通讯作者：
Namba, M
影响因子：
6.4
作者：
Kawasaki, K.;Watanabe, M.;Date, H.
通讯作者：
Date, H.