Does Ras/Rho Have Skin in the Game: The Importance of the Isoprenoid Biosynthesis Pathway in Merkel Cell Carcinoma Cell Lines.

Merkel cell carcinoma (MCC) is a rare malignancy of the skin caused by Merkel cell polyomavirus (80% of cases) or by ultraviolet (UV) sun exposure (20% of cases). The isoprenoid biosynthesis pathway (IBP) is an essential metabolic pathway shown to be upregulated in tumorigenesis, causing aberrant activation of Ras and Rho GTPases and resulting in unregulated cellular proliferation and survival. Through the use of pharmacological inhibitors of the IBP, we assessed the role of the IBP and its downstream targets in viral-positive and viral-negative MCC cell lines. To identify the most critical IBP intermediates, cellular metabolic activity, cell death and cell cycle distribution were measured after IBP perturbation. Across all cell lines, treatment with IBP inhibitors, especially fluvastatin, decreased metabolic activity; however, perturbation of different intermediates resulted in variable responses between viral-positive and viral-negative cell lines. Our findings demonstrate varying dependence on the IBP between viral-positive and viral-negative MCC and highlight the importance of cellular dynamics when determining a treatment regimen for patients with MCC.