Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

Abstract

Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.

Keywords: SREBP1; lipogenesis; metastasis; obesity; ovarian cancer.

Figure 1

Transcoelomic dissemination model of ovarian cancer metastasis. (1) Ovarian cancer cells are exfoliated from the primary ovarian surface or fallopian tubes into the peritoneal cavity. (2) These detached single cells and multicellular aggregates (MCAs or spheroids) float in the peritoneal fluid or ascites and disseminate throughout the peritoneal cavity, as depicted by the blue arrows. Ovarian cancer cells and MCAs adhere to and implant on the peritoneum and peritoneal organs such as the omentum (3), where they clear the mesothelial lining (4), invade into the submesothelial extracellular matrix (ECM) (5), migrate and proliferate to form multiple distal metastatic tumors (6).

Figure 2

Domain structure of human sterol regulatory element binding proteins (SREBPs). Each SREBP precursor (SREBP1a, SREBP1c and SREBP2) shares a similar hairpin-like structure containing about 1150 amino acids (~125 KDa) and is organized into three domains: (1) an NH2-terminal cytoplasmic domain of about 480 amino acids (~68 KDa) that consist of an acidic transcriptional activation domain and a basic helix-loop-helix-leucine zipper (bHLH-Zip) DNA binding domain; (2) a central hydrophobic region containing two transmembrane segments that project into the ER lumen; (3) and a COOH-terminal cytoplasmic regulatory domain of about 590 amino acids. The NH2-terminal nuclear forms of mature SREBPs (nSREBPs) are generated by the two sequential proteolytic cleavages within the central region of the precursors upon sterol depletion.

Figure 3

Schematic illustration of sterol-regulated proteolytic activation of SREBPs. Right: Under conditions when intracellular sterol levels are elevated, it directly binds to the sterol-sensing domain (SSD) of SCAP, causing a conformational change in SCAP which triggers SCAP bind to another ER-resident membrane protein INSIG. The association of SREBP-SCAP-INSIG ternary complex results in retention of SREBP precursors in the ER and prevents the movement of SREBP-SCAP complex to the Golgi, thus inhibiting the proteolytic maturation of SREBP in the Golgi. Left: In the absence of sterol, INSIG is no longer associated with SREBP-SCAP in the ER (1), and SREBP-SCAP complex is loaded into COPII vesicles which bud out of the ER membrane (2) and subsequently fuse with the Golgi apparatus (3). In the Golgi, Site-1 Protease (S1P) carries out the first proteolytic cleavage (scissor) in the intra-luminal loop of SREBPs between the two membrane-spanning sequences (4). Once the two halves of the SREBP are separated, a Golgi intramembrane metalloprotease Site-2 Protease (S2P) accomplishes the second cleavage (scissor) at a site located within the membrane-spanning region in the NH2-terminal domain of SREBP, releasing the bHLH-Zip domain which represents the mature SREBP (nSREBP) (5). Two nSREBP fragments dimerize and interact with importin β (6), and translocate to the nucleus (7) where nSREBP bind to sterol regulatory element (SRE) sequences as a dimer to gene promoter/enhancer regions and activate target genes that control synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids (8). SREBP, sterol regulatory element-binding protein; SCAP, SREBP cleavage-activating protein; SSD, sterol-sensing domains; WD: Tryptophan-Aspartate repeat motif; INSIG, insulin-induced gene; COPII, coat protein II; ER, endoplasmic reticulum; S1P, site-1 protease; S2P, site-2 protease; SRE, sterol regulatory element.

Figure 4

Downstream target genes of SREBPs. The homo- and heterodimerized nSREBPs (-1a, -1c and -2) enter the nucleus, in combination with other coactivators, bind to sterol regulatory elements (SREs) in the promoters/enhancers and activate transcription of target genes. SREBP-1a, -1c specifically activate genes involved in fatty acid synthesis, such as ACLY, ACC, FASN and SCD1. SREBP2 preferentially targets genes involved in cholesterol biosynthesis, such as LDLR, HMGCR, HMGCS, and MVD. INSIGs are negative regulators of SREBP proteolysis, while the INSIG1 gene itself is a target of the nSREBPs. Thus INSIG1 is also regulated by SREBPs. As a target gene of itself, SREBPs mRNA can be induced and regulated by nSREBPs as well. ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; HMGCS, HMG-CoA synthase; HMGCR, HMG-CoA reductase; LDLR, low density lipoprotein receptor; MVD, diphosphomevalonate decarboxylase; INSIG1, insulin-induced gene 1.