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Kaid Johar, Dhaval Shukal, Abhay Vasavada, Aditya Sudhalkar; Dichloroacetate prevents abnormal proliferation and differentiation of retina pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5326.
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© ARVO (1962-2015); The Authors (2016-present)
Abnormal proliferation and differentiation of Retina Pigment Epithelial (RPE) cells is associated with proliferative vitroretinopathy, diabetic retinopathy, etc. Earlier studies have shown that dichloroacetate (DCA) prevents the proliferation, differentiation and migration of several cancer cell lines. We hypothesize that DCA can also prevent the abnormal proliferation and differentiation of RPE cells. The study is designed to evaluate the effect of DCA on the proliferation, differentiation and migration of RPE cells induced by transforming growth factor β (TGFβ).
RPE cell line, ARPE-19 was exposed to various concentrations of DCA for 24 hour followed by 5ng/ml TGFβ2 for 24 hours. qPCR, western blotting and immunofluorescence analysis were used to evaluate effect of DCA. Cell viability was evaluated by MTT and calcein AM/propidium iodide assay. Migration ability of cells was evaluated by wound healing and transwell plate assay. Proliferation was evaluated by expression of PCNA. Mitochondrial depolarization was evaluated by JC1. Akt/PI3K, Erk/MAPK and AMPK pathways were evaluated as a mediator of cell differentiation programe.
DCA from 1 mM to 100 mM was found to be non-toxic to ARPE-19 calls. DCA exposure reduced the migration of cells which was otherwise induced by TGFβ2 as revealed by both wound healing and transwell assay. DCA also reduced proliferation of ARPE-19 cells. DCA exposure leads to increased expression of mitochondria and it also increased the membrane potential of mitochondria. Low concentration of DCA promoted expression of markers associated with abnormal differentiation of RPE cells while high concentration of DCA inhibited. DCA exposure up-regulated the level of pAMPK in compare to AMPK, reduced the level of pErk compared to Erk and reduced the level of pAkt compared to Akt.
The effect of DCA on TGFβ induced abnormal differentiation of RPE cells is dose dependent, promoting at low concentration while inhibiting at higher concentration and is mediated by PI3k/Akt, Erk/MAPK and AMPK pathway.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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