Role of Intracellular Lipid Binding Proteins in Cancer Progression
Creators: Choi, Won Shik
Publisher: name: University of Alberta Library
Year: 2024

<p>Intracellular lipid-binding proteins (iLBPs) are transporters of lipophilic molecules in aqueous cellular environments. To date, ten fatty acid-binding proteins (FABPs), four cellular retinol-binding proteins (CRBPs) and two cellular retinoic acid-binding proteins (CRABPs) have been identified as members of iLBP family. iLBPs serve a central role in lipid homeostasis and lipid metabolism. Lipid metabolism is often dysregulated in various cancers and is characterized by increased lipogenesis, lipid uptake, lipid accumulation and fatty acid oxidation. Despite the importance of lipid metabolism in cancer biology and upregulation of iLBPs in specific cancer types, the role of iLBPs in cancer progression remains an understudied area of research. <br>
    Glioblastoma (GBM) is the most common and deadly type of brain cancer with only ~5% of patients diagnosed with GBM still alive 5 years after diagnosis. Despite aggressive standard treatment which includes surgical resection and concurrent radiotherapy and temozolomide chemotherapy, GBM tumours invariably recur in the brain with additional therapies of no proven benefit. The highly infiltrative nature of GBM and the presence of GBM stem-like cells (GSCs) have been shown to contribute to the therapeutic challenges associated with this tumour and GBM recurrence. Clearly, better treatment strategies that specifically target infiltrative cells and GSCs will be required to improve clinical outcome. In GBM tumour tissues, the tightly regulated balance between omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and omega-3 PUFA docosahexaenoic acid (DHA) that is characteristic of the adult brain is disrupted resulting in lower DHA levels relative to AA levels. In addition, expression of the radial glial stem cell marker FABP7 is induced in GBM. As FABP7 has previously associated with GBM cell infiltration and GSC populations, we hypothesize that supplementing DHA and/or inhibiting FABP7 may represent promising therapeutic approaches to improve GBM clinical outcome. In Chapter 2, we examine the role of FABP7 in the uptake of AA and DHA in patient-derived GSCs grown as neurosphere cultures and the effect of FABP7 and DHA on the migration of GSCs in vitro. We show that FABP7 increases DHA uptake in GSCs and demonstrate FABP7/DHA-dependent inhibition of GSC migration. In Chapter 3, we show that GBM cell migration is guided by ultra-long membrane-enclosed protrusions called tumour microtubes (TMs) which serve as structural support for directional cell migrations. FABP7 knockdown in GSCs inhibits TM production. We propose that TMs are analogous to the radial glial fiber network produced by FABP7-expressing radial glial cells that guide long distance neuronal migrations in the developing brain. TMs have previously been implicated in the formation of cell-to-cell connections to form therapy-resistant network in orthotopic mouse models of GBM. We show that pharmacological inhibition of FABP7 interferes with TM formation, suggesting that FABP7 inhibition, in combination with currently treatment modalities, may represent promising therapeutic strategies for GBM. <br>
    HER2-enriched (HER2+) breast cancers are characterized by amplification of the HER2 gene. HER2+ breast cancers often co-amplify the gene encoding retinoic acid receptor alpha (RARα), a key determinant of retinoic acid (RA) effectiveness. Thus, one would predict that RA represents a promising anti-cancer therapeutic agent for HER2+ breast cancers. It is therefore surprising that HER2+ breast cancers are generally refractory to RA treatment. As RARα is located at the cell nucleus and RA is a lipid soluble molecule, we hypothesize that RA binding proteins play a role in RA resistance in HER2+ breast cancer cells. In Chapter 4, we show that MYC is upregulated in HER2+ breast cancers and MYC suppresses expression of CRABP2, a key iLBP that delivers RA to RARα, to attenuate RA-mediated cytotoxicity. We propose that RA therapy may benefit HER2+ breast cancer patients with low levels of MYC. We further propose that targeting MYC in HER2+ breast cancer patients with elevated levels of MYC may sensitize these tumours to RA. </p>