Cell surface CD63 increased by up-regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032.

Abstract

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.

• Authors: Kohya Kudo, Atsuko Yoneda, Daiki Sakiyama, Kai Kojima, Takeki Miyaji, Miku Yamazaki, Saori Yaita, Takuya Hyodo, Reiko Satow, Kiyoko Fukami
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 3 Pg. 3851-3869 (03 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 30508500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Sugars
• Antineoplastic Agents
• Polysaccharides
• Tetraspanin 30
• polylactosamine
• Vemurafenib

Topics

• Amino Sugars (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Humans
• Melanoma (metabolism)
• Polysaccharides (metabolism)
• Protein Processing, Post-Translational
• Tetraspanin 30 (genetics, metabolism)
• Vemurafenib (pharmacology)