Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway.
Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway.
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顺铂在黑色素瘤细胞中诱导的衰老相关分泌因子通过激活 ERK1/2-RSK1 通路促进非衰老黑色素瘤细胞生长
DOI：
10.1038/s41419-018-0303-9
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发表时间：
2018-02-15
影响因子：
9
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Sun X;Shi B;Zheng H;Min L;Yang J;Li X;Liao X;Huang W;Zhang M;Xu S;Zhu Z;Cui H;Liu X
尽管靶向治疗和免疫治疗大大改善了黑色素瘤的预后，但耐药性和低应答率仍然保持了传统化疗的不可替代性。顺铂(CDDP)广泛应用于不同类型的肿瘤，有效率高，但对黑色素瘤的疗效普遍较低。支撑这些现象的机制还没有得到充分的理解。在这里，我们证明了不同的黑色素瘤细胞系在CDDP处理后与其他类型的肿瘤细胞相比具有衰老表型。顺铂治疗通过DNA损伤反应和P53/P21通路的顺序激活诱导黑色素瘤A375细胞衰老。CDDP单独或CDDP与达卡巴肼联合诱导的衰老黑色素瘤细胞均表现出较强的衰老相关分泌表型(SASP)，即分泌多种细胞因子。IL-1α是SASP的早期成分和上游调节因子。同样，CDDP单独或与达卡巴肼合用均可诱导A375或B16F10黑色素瘤移植瘤小鼠黑色素瘤细胞衰老和SASP。衰老A375细胞上清液通过激活ERK1/2-RSK1通路，促进正常非衰老A375细胞的生长，增强其IL-8的表达和分泌。将非衰老和衰老的A375细胞一起移植到裸鼠体内，与单独移植非衰老细胞相比，肿瘤生长速度加快；单独移植衰老细胞时不会出现肿瘤。在A375荷瘤小鼠体内注射顺铂后，针对SASP因子IL-1α或IL-8的中和抗体明显延缓了肿瘤的生长。结果提示，CDDP诱导的衰老黑色素瘤细胞通过SASP因子激活ERK1/2-RSK1通路促进非衰老细胞的增殖。细胞衰老和伴随的SASP可能是黑色素瘤抵抗化疗的特殊机制。
Although targeted therapy and immunotherapy greatly improve the outcome of melanoma, drug resistance and low response rates still maintain the unsubstitutability of traditional chemotherapy. Cisplatin (CDDP) is widely used in different types of tumours with high response rates, but it generally has low efficiency in melanoma. The mechanisms underpinning the phenomena are not sufficiently understood. Here we demonstrated that various melanoma cell lines adopted senescence phenotype after CDDP treatment in contrast to the other types of tumour cells. CDDP treatment induced melanoma A375 cells into senescence through the sequential activation of the DNA damage response and the P53/P21 pathway. All the senescent melanoma cells induced by CDDP alone or the combination of CDDP and dacarbazine developed robust senescence-associated secretory phenotype (SASP), that is, the secretion of multiple cytokines. IL-1α was an early component and an upstream regulator of SASP. Similarly, CDDP either alone or combined with dacarbazine could induce melanoma cell senescence and SASP in either A375 or B16F10 melanoma xenograft mice. The supernatant of senescent A375 cells promoted the growth of normal non-senescent A375 cells and enhanced their expression and secretion of IL-8 through the activation of the ERK1/2-RSK1 pathway. The transplantation of non-senescent and senescent A375 cells together into nude mice showed accelerated tumour growth compared with transplanting non-senescent cells alone; no tumours developed when transplanting senescent cells alone. Following CDDP administration in A375-bearing mice, the intratumour injection of neutralisation antibodies targeting the SASP factors IL-1α or IL-8 evidently delayed tumour growth. The results suggest that the CDDP-induced senescent melanoma cells promote non-senescent cells proliferation through the activation of ERK1/2-RSK1 pathway by the SASP factors. Cell senescence and concomitant SASP may be the particular mechanisms for melanoma to resist chemotherapeutics.
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DOI：
10.1126/science.1253735
发表时间：
2014-11-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lo JA;Fisher DE
通讯作者：
Fisher DE
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
影响因子：
10.5
作者：
Ohanna, Mickael;Giuliano, Sandy;Bertolotto, Corine
通讯作者：
Bertolotto, Corine
影响因子：
2.6
作者：
Alzoubi, Karem;Khabour, Omar;Al-Azzam, Sayer
通讯作者：
Al-Azzam, Sayer