Chondroitin sulfate proteoglycan-4 does not protect melanoma cells during inhibition of PI3K and mTOR pathways.
BACKGROUND
Chondroitin sulfate proteoglycan-4 (CSPG4) is commonly expressed in melanoma cells and induces melanoma cell proliferation and migration by enhancement of activation of the extracellular signal-regulated kinase 1, 2 (ERK1,2) pathway. The phosphoinositide 3-kinase (PI3K) -protein kinase B (AKT) and mammalian target of rapamycin (mTOR) pathways are also frequently de-regulated in melanoma. We hypothesized that CSPG4, by sustained activation of PI3K, may reduce the effect of the dual inhibition of PI3K-AKT and mTOR pathways.


METHODS
CSPG4-negative melanoma cell line WM1552C was transfected with CSPG4 and CSPG4 lacking cytoplasmic domain (melanoma-associated chondroitin sulfate proteoglycan (MCSP)ΔCD). To assess the effect of CSPG4 on the mTOR pathway, PF-5212384, a dual PI3K/mTOR inhibitor was used. Cell proliferation and downstream signaling from mTOR was assayed in the presence of CSPG4.


RESULTS
Forced CSPG4 expression did not provide any protection to melanoma cells from the pharmacological inhibition of mTOR pathway in vitro. In addition, we demonstrated that inhibition of signaling molecules downstream of AKT and mTOR was not diminished in the presence of CSPG4 when the cells were treated with the PI3K/mTOR inhibitor.


CONCLUSIONS
CSPG4 expression does not have any impact on survival and signaling activity of melanoma cells during PI3K/mTOR inhibition.
University of Minnesota School of Dentistry, Minneapolis, MN, U.S.A.
Sehrish
S
Javaid
University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, U.S.A.
Kaoru
K
Terai
University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, U.S.A. adudek@uic.edu.
Arkadiusz Z
AZ
Dudek
D000941:Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans; D058570:TOR Serine-Threonine Kinases; D000099216:Chondroitin Sulfate Proteoglycan 4; C546842:MTOR protein, human
Chondroitin sulfate proteoglycan-4; PI3K; mTOR; melanoma