Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice
Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice
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DOI：
10.4161/cbt.29684
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发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Hrelia, Patrizia
中科院分区：
文献类型：
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作者：
Bergantin, Elisa;Quarta, Carmelo;Hrelia, Patrizia
横纹肌肉瘤(RMS)是儿童最常见的软组织肉瘤，分为胚胎型(ERMS)和肺泡型(ARM)，后者预后最差。我们报道了萝卜硫素(SFN)，一种从西兰花中提取的抗癌异硫氰酸酯，可引起ERMS和ARM细胞的生长抑制和凋亡，并呈剂量和时间依赖性。在ARM中，SFN诱导关键基因和蛋白表达的调节：PAX3-FKHR、MYCN和MET的mRNA和蛋白水平下降，而p21和TRAIL受体DR5(而不是DR4)的mRNA和蛋白水平上升。由于DR5在ARM中的表达增加，我们用TRAIL、SFN或它们的组合处理ARM细胞。当ARM细胞(RH30和RH4)被证明是TRAIL耐药的时候，SFN恢复了它们对TRAIL诱导的细胞生长抑制的敏感性，导致联合TRAIL的作用更强。转染siDR5的ARM细胞显示，SFN诱导的DR5是一个关键的调节因子，与TRAIL诱导的细胞生长抑制直接相关。通过microPET检测SFN和TRAIL的体内抗肿瘤活性。结果表明，SFN或TRAIL作为单一药物对小鼠的全身治疗(3wk)仅延缓了肿瘤的进展，而SFN和TRAIL的联合治疗则导致肿瘤的消除。这些结果表明，SFN在肺泡型和胚胎型横纹肌肉瘤中都触发了凋亡通路，SFN和TRAIL联合治疗侵袭性肺泡型可能是一种有前途的治疗方法。
Rhadbomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is subdivided in the embryonal (ERMS) and alveolar (ARMS) subtypes, the latter being associated with the worst prognosis.We report that sulforaphane (SFN), a broccoli-derived anticancer isothiocyanate, causes dose- and time-dependent growth inhibition and apoptosis in both ERMS and ARMS cells. In ARMS, SFN induced the modulation of expression of crucial genes and proteins: mRNA and protein levels of PAX3-FKHR, MYCN, and MET decreased, while those of p21 and TRAIL-receptor DR5 (but not DR4) increased. Since DR5 expression increased specifically in ARMS, we treated ARMS cells with TRAIL, SFN, or their combination. While ARMS cells (RH30 and RH4) proved to be TRAIL-resistant, SFN restored their sensitivity to TRAIL-induced cell-growth inhibition, leading to a stronger effect in combination with TRAIL. ARMS cells transfected with siDR5 showed that SFN-induced DR5 acts as a key regulator, being directly related to the TRAIL-induced cell-growth inhibition. The in vivo anti-tumor activity of SFN and TRAIL was evaluated in a xenograft murine model of ARMS through microPET. The results showed that the systemic treatment (3 wk) of mice with SFN or TRAIL as single agents only delayed tumor evolution, while the combined treatment of SFN and TRAIL led to tumor elimination. These findings indicate that SFN triggers the apoptotic pathway in both alveolar and embryonal rhabdomyosarcomas and that combined treatment with SFN and TRAIL might be a promising therapy for the aggressive alveolar subtype.