Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway

Xuerong Sun,Hongjing Cui,Jie Yang,Mingmeng Zhang,Weixing Huang,Ling Min,Benyan Shi,Xinguang Liu,Xiaoyi Li,Shun Xu,Zhe Zhu,Huiling Zheng,Xiaoxin Liao

doi:10.1038/s41419-018-0303-9

Abstract

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.

Highlights

Melanoma consistently shows increased incidence almost all over the world[1]
We investigated the effect of CDDP on several types of tumour cells and revealed that melanoma is inclined to enter into senescence
To observe the effect on melanoma, CDDP was added to the growth medium of A375 cells at various final concentrations. 24 h later, CDDP was removed and detections were performed at different time points (Fig. 1a)

Summary

Introduction

The established risk factors for melanoma include family history, multiple moles, fair skin, ultraviolet radiation and immunosuppression[2]. Drug therapy is essential for metastatic melanoma. The targeted inhibitors of BRAF (vemurafenib) or MEK (binimetinib) have shown improved survival and response rates in metastatic melanoma[3,4,5]. Immune checkpoint inhibitors, such as PD-1 antibody and CTLA-4 antibody, produce striking durable responses and curative outcomes[2,6]. Both targeted therapies and immunotherapies have obvious limitations, such as drug resistance and improved but still low response rates[7,8]. Traditional chemotherapies are still indispensable in melanoma therapy 10

Methods

Results

Conclusion