P38 MAPK activation through B7-H3-mediated DUSP10 repression promotes chemoresistance

Karine Flem-Karlsen,Øystein Fodstad,Vivi A Flørenes,Tove Øyjord,Caroline E Nunes-Xavier,Christina Tekle,Gunhild M Mælandsmo

doi:10.1038/s41598-019-42303-w

Karine Flem-Karlsen, Øystein Fodstad + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-42303-w

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Abstract

Immunoregulatory protein B7-H3 is involved in the oncogenic and metastatic potential of cancer cells, as well as in drug resistance. Resistance to conventional chemotherapy is an important aspect of melanoma treatment, and a better understanding of how B7-H3 enhances drug resistance may lead to the development of more effective therapies. We investigated the in vitro and in vivo sensitivity of chemotherapeutic agents dacarbazine (DTIC) and cisplatin in sensitive and drug resistant melanoma cells with knockdown expression of B7-H3. We found that knockdown of B7-H3 increased in vitro and in vivo sensitivity of melanoma cells to the chemotherapeutic agents dacarbazine (DTIC) and cisplatin, in parallel with a decrease in p38 MAPK phosphorylation. Importantly, in B7-H3 knockdown cells we observed an increase in the expression of dual-specific MAP kinase phosphatase (MKP) DUSP10, a MKP known to dephosphorylate and inactivate p38 MAPK. DUSP10 knockdown by siRNA resulted in a reversion of the increased DTIC-sensitivity seen in B7-H3 knockdown cells. Our findings highlight the potential therapeutic benefit of combining chemotherapy with B7-H3 inhibition, and indicate that B7-H3 mediated chemoresistance in melanoma cells is driven through a mechanism involving DUSP10-mediated inactivation of p38 MAPK.

Highlights

B7-H3, a member of the B7 family of immune checkpoint proteins, is upregulated in many different cancer types[1], and B7-H3 targeted therapy is currently being tested in several clinical trials[2]
To determine if the B7-H3 associated drug resistance might involve effects asserted by stress signaling, we treated melanoma cells with two chemotherapeutic agents, DTIC and cisplatin
Our results suggest that B7-H3 suppresses the expression of DUSP10 at the mRNA level, which in turn leads to higher p38 mitogen activated protein kinase (MAPK) activation and increases tumor cell resistance to chemotherapy (Fig. 6)

Summary

Introduction

B7-H3, a member of the B7 family of immune checkpoint proteins, is upregulated in many different cancer types[1], and B7-H3 targeted therapy is currently being tested in several clinical trials[2]. The MAPK pathways regulate various cellular processes, such as proliferation, differentiation, apoptosis and stress responses, and include four major pathways, as defined by their MAPK effector: ERK1/2, ERK5, JNKs and p38s MAPK6. The p38 MAPK pathway can phosphorylate a wide range of proteins. This include activating phosphorylation of various transcription factors that may, amongst many physiological processes, lead to the maintenance of a tumor aggressive phenotype and/or resistance to chemotherapy[8]. Despite the recent advances in melanoma treatment, dacarbazine (DTIC) chemotherapy is still being widely used even though its response rate as a single agent is only 10–20%14,15. DTIC treatment combined with targeted therapy may improve the overall response, and is a promising way forward for treatment of metastatic melanoma[16]

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