Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; and.
Advanced Research and Development Programs for Medical Innovation (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan.
FASEB J. 2019 Mar;33(3):3851-3869. doi: 10.1096/fj.201800664RR. Epub 2018 Dec 3.
The BRAF inhibitor PLX4032 is effective in treating BRAF-mutated melanoma; however, because drug resistance develops in most cases, it is critical to develop a new strategy for inhibiting drug-resistant melanoma growth. The melanoma-associated membrane glycoprotein CD63 is involved in cell proliferation and metastasis. Here, we found that cell surface CD63 suppresses the proliferation of human melanoma cells and PLX4032-resistant cells. Endogenous CD63 protein levels were negatively correlated with PLX4032 resistance of human melanoma cell lines. CD63 overexpression in these cells, in which endogenous CD63 levels are low, suppressed cell proliferation under PLX4032 treatment. The cell surface levels and average molecular mass of CD63 were increased with PLX4032 treatment because of the up-regulated polylactosamine modification caused by induced β1,3- N-acetylglucosaminyltransferase 2 expression, which is involved in polylactosamine synthesis. Forced cell surface localization of CD63 led to reduced melanoma cell proliferation without PLX4032 treatment. CD63 overexpression in PLX4032-resistant cells, in which CD63 levels were lower and cell surface polylactosamine levels were higher than those in parental cells, effectively suppressed proliferation. Our study shows the potential of CD63 to sensitize melanoma cells to PLX4032 and to reduce the proliferation of PLX4032-resistant cells.-Kudo, K., Yoneda, A., Sakiyama, D., Kojima, K., Miyaji, T., Yamazaki, M., Yaita, S., Hyodo, T., Satow, R., Fukami, K. Cell surface CD63 increased by up-regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032.
BRAF 抑制剂 PLX4032 对治疗 BRAF 突变型黑色素瘤有效；然而，由于大多数情况下会产生耐药性，因此开发抑制耐药性黑色素瘤生长的新策略至关重要。黑色素瘤相关膜糖蛋白 CD63 参与细胞增殖和转移。在这里，我们发现细胞表面 CD63 抑制人黑色素瘤细胞和 PLX4032 耐药细胞的增殖。内源性 CD63 蛋白水平与人类黑色素瘤细胞系对 PLX4032 的耐药性呈负相关。在这些细胞中，内源性 CD63 水平较低时，CD63 的过表达抑制了 PLX4032 处理下的细胞增殖。由于诱导的β1,3-N-乙酰氨基葡萄糖基转移酶 2 表达引起的多乳糖胺修饰上调，导致 PLX4032 处理后 CD63 的细胞表面水平和平均分子量增加，该酶参与多乳糖胺合成。CD63 的强制细胞表面定位导致未经 PLX4032 处理的黑色素瘤细胞增殖减少。PLX4032 耐药细胞中 CD63 的过表达，其 CD63 水平较低，细胞表面多乳糖胺水平高于亲本细胞，有效地抑制了增殖。我们的研究表明 CD63 具有使黑色素瘤细胞对 PLX4032 敏感和降低 PLX4032 耐药细胞增殖的潜力。-Kudo，K.，Yoneda，A.，Sakiyama，D.，Kojima，K.，Miyaji，T.，Yamazaki，M.，Yaita，S.，Hyodo，T.，Satow，R.，Fukami，K. 通过上调的多乳糖胺修饰增加的细胞表面 CD63 使人类黑色素瘤细胞对 BRAF 抑制剂 PLX4032 敏感。
