Penta-O-galloyl-β-D-glucose Suppresses Prostate Cancer Bone Metastasis by Transcriptionally Repressing EGF-Induced MMP-9 Expression
Penta-O-galloyl-β-D-glucose Suppresses Prostate Cancer Bone Metastasis by Transcriptionally Repressing EGF-Induced MMP-9 Expression
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DOI：
10.1021/jf803725h
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发表时间：
2009-04-22
影响因子：
6.1
通讯作者：
Way, Tzong-Der
中科院分区：
文献类型：
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作者：
Kuo, Po-Tsun;Lin, Tsung-Pang;Way, Tzong-Der
前列腺癌是最常见的恶性肿瘤，也是美国男性癌症相关死亡的第二大原因。骨组织产生的表皮生长因子（EGF）通过刺激前列腺癌细胞分泌基质金属蛋白酶（MMP）而促进前列腺癌转移。在这项研究中，通过将不同浓度的五-O-没食子酰-β-D-葡萄糖（5GG）与2 × 10（4）PC-3细胞孵育48 h进行体外侵袭试验。采用MTT法和Western blot法检测了5GG对人雄激素非依赖性前列腺癌PC-3细胞的抗侵袭和细胞毒作用。5GG通过降低MMP-9的转录活性，以剂量和时间依赖的方式抑制EGF诱导的细胞侵袭力和MMP-9的表达。为了探讨5GG介导的MMP-9调节机制，我们进一步检测了5GG对转录因子，包括NF-κ B B、AP-1和丝裂原活化蛋白激酶（MAPK）活性的影响。结果表明，5 GG可抑制EGF介导的NF-κ B核转位，并抑制EGF介导的NF-κ B上游调控因子c-jun N-末端激酶（JNK）的活化。此外，我们发现5GG通过蛋白酶体途径降低EGFR表达。这些结果表明，5GG可以发挥至少部分的雄激素非依赖性前列腺癌的抗侵袭作用，通过控制MMP-9的表达，通过抑制EGFR/JNK途径。最后，5GG抑制裸鼠胫骨内注射PC-3细胞的侵袭和肿瘤发生。这些体外和体内结果表明，5GG可能是治疗晚期前列腺癌的治疗候选者。
Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of cancer-related death of men in the United States. Epidermal growth factor (EGF) generated from bone tissue contributes to prostate cancer metastasis through stimulating matrix metalloproteinase (MMP) secretions from prostate cancer cells. In this study, in vitro invasion assay was performed by incubating penta-O-galloyl-beta-D-glucose (5GG) at various concentrations with 2 x 10(4) PC-3 cells for 48 h. The anti-invasive and cytotoxic effects of 5GG were found and evaluated on the human androgen-independent prostate cancer PC-3 cell line by MTT assays and Western blot analyses. 5GG inhibited the EGF-induced cell invasiveness and MMP-9 expression in a dose- and time-dependent manner by reducing the MMP-9 transcriptional activity. To explore the mechanisms for the 5GG-mediated regulation of MMP-9, we further examined the effects of 5GG on transcription factors, including NF-kappa B, AP-1, and mitogen-activated protein kinase (MAPK) activities. The results showed that 5GG suppressed the EGF-incluced NF-kappa B nuclear translocation and also abrogated the EGF-incluced activation of c-jun N-terminal kinase (JNK), an upstream modulator of NF-kappa B. Moreover, we showed that 5GG reduced EGFR expression through the proteasome pathway. These results suggest that 5GG may exert at least part of its anti-invasive effect in androgen-independent prostate cancer by controlling MMP-9 expression through the suppression of the EGFR/JNK pathway. Finally, 5GG suppresses invasion and tumorigenesis in nude mice treatment with intratibia injection of PC-3 cells. These in vitro and in vivo results suggest that 5GG may be a therapeutic candidate for the treatment of advanced prostate cancer.