Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Sci Rep. 2019 Apr 9;9(1):5839. doi: 10.1038/s41598-019-42303-w.
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.
免疫调节蛋白 B7-H3 参与癌细胞的致癌和转移潜能，以及耐药性。对常规化疗的耐药性是黑色素瘤治疗的一个重要方面，更好地了解 B7-H3 如何增强耐药性可能会导致更有效的治疗方法的发展。我们研究了敲低 B7-H3 表达对敏感和耐药黑色素瘤细胞中化疗药物达卡巴嗪（DTIC）和顺铂的体外和体内敏感性。我们发现，B7-H3 的敲低增加了黑色素瘤细胞对化疗药物达卡巴嗪（DTIC）和顺铂的体外和体内敏感性，同时降低了 p38 MAPK 的磷酸化。重要的是，在 B7-H3 敲低细胞中，我们观察到双特异性 MAP 激酶磷酸酶（MKP）DUSP10 的表达增加，DUSP10 是一种已知能够去磷酸化和失活 p38 MAPK 的 MKP。用 siRNA 敲低 DUSP10 导致 B7-H3 敲低细胞中观察到的 DTIC 敏感性增加的逆转。我们的研究结果强调了将化疗与 B7-H3 抑制相结合的潜在治疗益处，并表明黑色素瘤细胞中 B7-H3 介导的化疗耐药性是通过涉及 DUSP10 介导的 p38 MAPK 失活的机制驱动的。
