PMID- 28924047 OWN - NLM STAT- MEDLINE DCOM- 20180123 LR - 20240102 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 47 DP - 2017 Nov 24 TI - Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice. PG - 19198-19208 LID - 10.1074/jbc.M116.773093 [doi] AB - Tumors depend on their microenvironment for sustained growth, invasion, and metastasis. In this environment, endothelial cells (ECs) are an important stromal cell type interacting with malignant cells to facilitate tumor angiogenesis and cancer cell extravasation. Of note, lysosomal acid lipase (LAL) deficiency facilitates melanoma growth and metastasis. ECs from LAL-deficient (lal(-/-)) mice possess enhanced proliferation, migration, and permeability of inflammatory cells by activating the mammalian target of rapamycin (mTOR) pathway. Here we report that lal(-/-) ECs facilitated in vivo tumor angiogenesis, growth, and metastasis, largely by stimulating tumor cell proliferation, migration, adhesion, and transendothelial migration via increased expression of IL-6 and monocyte chemoattractant protein 1 (MCP-1). This prompted us to look for lysosomal proteins that are involved in lal(-/-) EC dysfunctions. We found that lal(-/-) ECs displayed increased expression of Rab7, a late endosome/lysosome-associated small GTPase. Moreover, Rab7 and mTOR were co-increased and co-localized to lysosomes and physically interacted in lal(-/-) ECs. Rab7 inhibition reversed lal(-/-) EC dysfunctions, including decreasing their enhanced migration and permeability of tumor-stimulatory myeloid cells, and suppressed EC-mediated stimulation of in vitro tumor cell transmigration, proliferation, and migration and in vivo tumor growth and metastasis. Finally, Rab7 inhibition reduced overproduction of reactive oxygen species and increased IL-6 and MCP-1 secretion in lal(-/-) ECs. Our results indicate that metabolic reprogramming resulting from LAL deficiency enhances the ability of ECs to stimulate tumor cell proliferation and metastasis through stimulation of lysosome-anchored Rab7 activity. CI - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Zhao, Ting AU - Zhao T AD - From the Department of Pathology and Laboratory Medicine and. FAU - Ding, Xinchun AU - Ding X AD - From the Department of Pathology and Laboratory Medicine and. FAU - Yan, Cong AU - Yan C AD - From the Department of Pathology and Laboratory Medicine and coyan@iupui.edu. AD - Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202. FAU - Du, Hong AU - Du H AD - From the Department of Pathology and Laboratory Medicine and hongdu@iupui.edu. AD - Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202. LA - eng GR - R01 CA138759/CA/NCI NIH HHS/United States GR - R01 CA152099/CA/NCI NIH HHS/United States GR - R01 CA225108/CA/NCI NIH HHS/United States GR - R01 HL087001/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20170918 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Reactive Oxygen Species) RN - 0 (rab7 GTP-Binding Proteins) RN - 0 (rab7 GTP-binding proteins, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.1.13 (Sterol Esterase) RN - EC 3.1.1.13 (lysosomal acid lipase, mouse) RN - EC 3.6.5.2 (rab GTP-Binding Proteins) SB - IM MH - Animals MH - Apoptosis MH - Carcinoma, Lewis Lung/genetics/metabolism/*secondary MH - Cell Movement MH - Cell Proliferation MH - Endothelium, Vascular/*enzymology/pathology MH - Lysosomes/*enzymology MH - Melanoma, Experimental/genetics/metabolism/*secondary MH - Mice MH - Mice, Knockout MH - Myeloid Cells/metabolism/pathology MH - Neoplasm Invasiveness MH - Neoplasm Metastasis MH - Reactive Oxygen Species MH - Signal Transduction MH - Sterol Esterase/*physiology MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Transendothelial and Transepithelial Migration MH - Tumor Cells, Cultured MH - Wolman Disease/*complications/physiopathology MH - rab GTP-Binding Proteins/genetics/*metabolism MH - rab7 GTP-Binding Proteins PMC - PMC5702662 OTO - NOTNLM OT - Rab7 GTPase OT - cancer therapy OT - endothelial cell OT - lysosomal acid lipase OT - lysosome OT - tumor metastasis OT - tumor microenvironment COIS- The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health EDAT- 2017/09/20 06:00 MHDA- 2018/01/24 06:00 PMCR- 2018/11/24 CRDT- 2017/09/20 06:00 PHST- 2016/12/19 00:00 [received] PHST- 2017/08/11 00:00 [revised] PHST- 2017/09/20 06:00 [pubmed] PHST- 2018/01/24 06:00 [medline] PHST- 2017/09/20 06:00 [entrez] PHST- 2018/11/24 00:00 [pmc-release] AID - S0021-9258(20)32892-1 [pii] AID - M116.773093 [pii] AID - 10.1074/jbc.M116.773093 [doi] PST - ppublish SO - J Biol Chem. 2017 Nov 24;292(47):19198-19208. doi: 10.1074/jbc.M116.773093. Epub 2017 Sep 18.