DGAT1 Inhibitor Suppresses Prostate Tumor Growth and Migration by Regulating Intracellular Lipids and Non-Centrosomal MTOC Protein GM130

Abstract

Acyl-CoA:diacylglycerol acyltransferase I (DGAT1) is a key enzyme in lipogenesis which is increased in metabolically active cells to meet nutrient requirements. DGAT1 has been recognized as an anti-obesity target; however, its role in the tumor microenvironment remains unclear. We postulated that, in prostate cancer (PCa) cells, augmented lipogenesis and growth are due to increased DGAT1 expression leading to microtubule-organizing center (MTOC) amplification. Thus, therapeutic targeting of DGAT1 potentially has tumor suppressive activity. We tested whether blocking DGAT1 in PCa cells altered MTOC and lipid signaling. Western blot and immunofluorescence were performed for MTOC and triglyceride mediators. Treatment with a DGAT1 inhibitor was evaluated. We found a stepwise increase in DGAT1 protein levels when comparing normal prostate epithelial cells to PCa cells, LNCaP and PC-3. Lipid droplets, MTOCs, and microtubule-regulating proteins were reduced in tumor cells treated with a DGAT1 inhibitor. Depletion of the non-centrosomal MTOC protein GM130 reduced PCa cell proliferation and migration. Inhibition of DGAT1 reduced tumor growth both in vitro and in vivo , and a negative feedback loop was discovered between DGAT1, PEDF, and GM130. These data identify DGAT1 as a promising new target for suppressing PCa growth by regulating GM130, MTOC number and disrupting microtubule integrity.

ELTD1 facilitates glioma proliferation, migration and invasion by activating JAK/STAT3/HIF-1α signaling axis

“…Immunofluorescence (IF) staining was performed as described previously 46,47 . Immunohistochemistry and semiquantitative scoring techniques were performed as described previously 48 .…”

The diversity and breadth of cancer cell fatty acid metabolism

“…We recently showed that pharmacological inhibition of DGAT1 in breast and prostate cancer cells blunted TG synthesis and influenced cell viability [ 3 , 4 ]. Likewise, knockdown of DGAT1 reduced lipid droplet number and cell proliferation and invasion of prostate cancer cells [ 135 , 247 ] and glioblastoma [ 246 ]. However, the protein levels of DGAT2 are reduced in HCC, and overexpression of DGAT2 inhibits cell proliferation and colony formation in vitro and tumor formation in vivo [ 248 ].…”

Improving the diversity of captured full-length isoforms using a normalized single-molecule RNA-sequencing method

“…8-9). DGAT1 encodes a key enzyme in lipogenesis, which was found increased in prostate cancer cells and could facilitate cell proliferation and migration 34 . DGAT1 gene expression was increased in both SRCCs and STADs (TCGA cohort) than non-malignant pairs, suggesting its increased expression in stomach adenocarcinoma universally.…”