Investigation of the role of chondroitin sulfate proteoglycan in causing treatment resistance in melanoma to PI3k/mTOR inhibition.

Abstract

Melanoma is one of the deadliest tumors. Despite the advances in understanding the melanoma cell biology and drug discoveries, treatment resistance remains a challenge. Chondroitin sulfate proteoglycan (CSPG4) is expressed on the surface of melanoma cells, and its role in metastatic progression has been established. One known mechanism responsible for this activity is modulation of the activity of ERK1,2. PI3k/mTOR pathway is also frequently deregulated in melanomas . We therefore investigated if CSPG4 has an impact on PI3K/mTOR pathway activity. Our results indicate that CSPG4 causes resistance to growth inhibition and apoptosis in early stage melanoma cell lines. The knockdown of CSPG4 sensitized the advanced disease stage cell lines to growth inhibition. CSPG4 also induced resistance at various levels of mTOR pathway in different cell lines, and resulted in inhibition of motility and invasion in response to treatment with PF-05212384, a potent PI3K/mTOR inhibitor. Melanoma cell lines derived from all stages of melanoma growth showed resistance to inhibition of 4ebp1. Our results indicate that CSPG4 play a role in decreased sensitivity of melanoma cells to mTOR pathway inhibition.