SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation.
SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation.
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DOI：
10.18632/oncotarget.3043
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Indovina P
中科院分区：
文献类型：
--
作者：
Casini N;Forte IM;Mastrogiovanni G;Pentimalli F;Angelucci A;Festuccia C;Tomei V;Ceccherini E;Di Marzo D;Schenone S;Botta M;Giordano A;Indovina P
最近的数据表明，SRC家族激酶（SFKs）可能是横纹肌肉瘤（RMS）的潜在治疗靶点，横纹肌肉瘤是儿童中最常见的软组织肉瘤。在这里，我们评估了最近开发的选择性SFK抑制剂（吡唑[3,4-d]嘧啶衍生物，称为SI221）对RMS细胞系的影响。SI221主要对SFK成员YES有效，显著降低细胞活力并诱导凋亡，不影响非肿瘤细胞，如原代人皮肤成纤维细胞和分化的C2C12细胞。此外，在RMS异种移植模型中，SI221降低了体外细胞迁移和侵袭，并降低了肿瘤生长。SFK抑制还通过影响NOTCH3受体-p38丝裂原活化蛋白激酶（MAPK）轴来诱导RMS细胞的肌肉分化，NOTCH3受体-p38丝裂原活化蛋白激酶（MAPK）轴调节增殖和分化之间的平衡。总之，我们的研究结果表明，SFK抑制，除了减少RMS细胞的生长和侵袭潜力，也可能是RMS的一种分化治疗策略。
Recent data suggest that SRC family kinases (SFKs) could represent potential therapeutic targets for rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. Here, we assessed the effect of a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221) on RMS cell lines. SI221, which showed to be mainly effective against the SFK member YES, significantly reduced cell viability and induced apoptosis, without affecting non-tumor cells, such as primary human skin fibroblasts and differentiated C2C12 cells. Moreover, SI221 decreased in vitro cell migration and invasion and reduced tumor growth in a RMS xenograft model. SFK inhibition also induced muscle differentiation in RMS cells by affecting the NOTCH3 receptor-p38 mitogen-activated protein kinase (MAPK) axis, which regulates the balance between proliferation and differentiation. Overall, our findings suggest that SFK inhibition, besides reducing RMS cell growth and invasive potential, could also represent a differentiation therapeutic strategy for RMS.
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影响因子：
3.7
作者：
Ma YC;Shi C;Zhang YN;Wang LG;Liu H;Jia HT;Zhang YX;Sarkar FH;Wang ZS
通讯作者：
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影响因子：
3.7
作者：
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通讯作者：
Komiya S
影响因子：
3.9
作者：
Lim, Min Jin;Seo, Yong Hak;Kim, Sung Soo
通讯作者：
Kim, Sung Soo
影响因子：
7.3
作者：
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通讯作者：
Botta, Maurizio
影响因子：
4
作者：
Ceccherini, Elisa;Indovina, Paola;Giordano, Antonio
通讯作者：
Giordano, Antonio