Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.
Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2S505phosphorylation. Conversely, HSulf-1 expression in SKOV3 cells reduced the number of LDs and increased the number of AVs compared to vector controls. Furthermore, pharmacological (AACOCF3) and ShRNA mediated downregulation of cPLA2 resulted in reduced LDs, and increased autophagy. Finally, in vivo experiment using OV202 Sh1 derived xenograft show that AACOCF3 treatment effectively attenuated tumor growth and LD biogenesis. Collectively, these results show a reciprocal regulation of autophagy and lipid biogenesis by HSulf-1 in ovarian cancer.
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Debarshi
D
Roy
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Susmita
S
Mondal
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Ashwani
A
Khurana
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Deok-Beom
DB
Jung
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Robert
R
Hoffmann
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Xiaoping
X
He
Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, USA.
Eleftheria
E
Kalogera
Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany.
Thomas
T
Dierks
Zucero Therapeutics. Brisbane, Queensland, Australia.
Edward
E
Hammond
Zucero Therapeutics. Brisbane, Queensland, Australia.
Keith
K
Dredge
Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Viji
V
Shridhar
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D001343:Autophagy; D016190:Carboplatin / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C081565:arachidonyltrifluoromethane; D016190:Carboplatin; C470791:SULF1 protein, human; D015238:Sulfotransferases; D054510:Phospholipases A2, Cytosolic