Abstract
Simple SummaryAlterations in cholesterol level play an important role in cancer development. Lipid transfer proteins (LTPs) are involved in cholesterol distribution between organelles. Among LTPs, some members of steroidogenic acute regulatory-related lipid transfer (START) protein family regulate the cholesterol transportation between organelles and have been revealed as critical for cancer development. This review highlights the recent discoveries of the StAR-related lipid transfer protein domain 3 (STARD3) member of START proteins in cancer development and progression. Blocking cholesterol transportation through the inhibition of STARD3 activity could be an important strategy to treat cancer.Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.
Highlights
Cancer, one of the leading causes of death worldwide [1], is a complex disease in which the number of cells increases uncontrollably
Various molecular-targeted agents have been approved by the US Food and Drug Administration (FDA), including small molecules and antibodies [12] used to target the proteasome [14], cyclin-dependent kinases (CDKs) [15], epidermal growth factor receptor (EGFR) [16], vascular endothelial growth factor (VEGF) [17], poly (ADP-ribose) polymerase (PARP) [18,19], and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) [20]
The electron-density maps reported by Horvath and coworkers for Steroidogenic acute regulatory (StAR)-related lipid transfer protein domain 3 (STARD3) (5I9J Protein Databank (PDB) code [146]) highlight two alternative conformations for Arg351—one of which is able to form a salt-bridge with Asp332 that partially blocks the internal cavity of the protein and could act as an allosteric trigger point in the communication with retinal proteins and enzymes involved with xanthophyll transport and metabolism [144]
Summary
One of the leading causes of death worldwide [1], is a complex disease in which the number of cells increases uncontrollably. There are published data that suggest that StAR-related lipid transfer domain-3 (STARD3), a membrane-targeted START protein, regulates the cholesterol accumulation in endosomes and mediates its inter-organelle distribution [40,41,42]. Intracellular cholesterol and lipid rafts are associated with an increasing number of oncogenic signals and proteins involved in cancer progression, cell invasion, and metastasis. Several works suggest the role of STARD10 in deregulating cell growth and tumorigenesis This protein is highly expressed in approximately 60% of human breast cancer cell lines, in 30% of primary breast carcinomas, and in mouse mammary tumors [110]. STARD15 has been considered a target to inhibit neoplastic cell growth This protein has been linked to cholesterol metabolism, as its activity increases when cholesterol synthesis is inhibited [91]. We will focus on STARD3 and discuss its role in cancer development
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