STARD3: A Prospective Target for Cancer Therapy

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.

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Sertoli Cell Expression of Steroidogenic Acute Regulatory Protein-Related Lipid Transfer 1 and 5 Domain-Containing Proteins and Sterol Regulatory Element Binding Protein-1 Are Interleukin-1β Regulated by Activation of c-Jun N-Terminal Kinase and Cyclooxygenase-2 and Cytokine Induction

Endocrinology ◽

10.1210/en.2005-0567 ◽

2005 ◽

Vol 146 (12) ◽

pp. 5100-5111 ◽

Cited By ~ 21

Author(s):

Tomomoto Ishikawa ◽

Keumsil Hwang ◽

Deborah Lazzarino ◽

Patricia L. Morris

Keyword(s):

Lipid Transfer Protein ◽

Regulatory Element ◽

Protein Domain ◽

Oxygen Species ◽

Lipid Transfer ◽

Transfer Protein ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Cox 2 ◽

Steroidogenic Acute Regulatory

In testicular Sertoli cells, IL-1β regulates steroid, lactate, and transferrin secretion; although each influences germ cell development and spermatogenesis, little is known about the signaling mechanisms involved. In other cell types, IL-1β potently induces reactive oxygen species and/or cyclooxygenase-2 (COX-2). In contrast, in Sertoli cells, IL-1β does not generate reactive oxygen species, but rapidly phosphorylates c-Jun-NH2-terminal kinase (JNK), but not p44/42 or p38 MAPK. Phosphorylated JNK stimulates COX-2 activity, mediating the expression of ILs and steroidogenic acute regulatory (StAR)-related (StAR-related lipid transfer protein domain containing) proteins D1 and D5, but not D4. In a time- and dose-dependent manner, IL-1β rapidly increases levels of COX-2 mRNA (2-fold); induction of COX-2 protein (50-fold) requires de novo protein synthesis. Concomitantly, increases in IL-1α, IL-6, and IL-1β mRNAs (1–3 h) are observed. As StAR-related lipid transfer protein domain containing protein 1 (StARD1) mRNA decreases, StARD5 mRNA increases; substantial recovery phase induction of StARD1 mRNA above control is noted (24 h). Inhibition of JNK or COX-2 activities prevents IL-1β induction of IL and StARD5 mRNAs and subsequent increases in StARD1 mRNA (24 h), indicating that these effects depend on the activation of both enzymes. StARD1 and D5 protein levels are significantly altered, consistent with posttranscriptional and posttranslational regulation. IL-1β rapidly decreases levels of precursor and mature sterol regulatory element-binding protein-1, changes not altered by cycloheximide, suggesting coordinate regulation of StARD1 and -D5, but not StARD4, expression. These data demonstrate that JNK and COX-2 activities regulate Sertoli cytokines and particularly START domain-containing proteins, suggesting protective stress responses, including transcription and protein and lipid regulation, within this specialized epithelium.

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Touché! STARD3 and STARD3NL tether the ER to endosomes

Biochemical Society Transactions ◽

10.1042/bst20150269 ◽

2016 ◽

Vol 44 (2) ◽

pp. 493-498 ◽

Cited By ~ 10

Author(s):

Léa P. Wilhelm ◽

Catherine Tomasetto ◽

Fabien Alpy

Keyword(s):

Lipid Transfer Protein ◽

Regulatory Protein ◽

Direct Interaction ◽

Lipid Transfer ◽

Membrane Contact Sites ◽

Late Endosomes ◽

Metabolite Exchange ◽

Membrane Contact ◽

Domain 3 ◽

Steroidogenic Acute Regulatory

Membrane contact sites (MCSs) are subcellular regions where the membranes of distinct organelles come into close apposition. These specialized areas of the cell, which are involved in inter-organelle metabolite exchange, are scaffolded by specific complexes. STARD3 [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain-3] and its close paralogue STARD3NL (STARD3 N-terminal like) are involved in the formation of contacts between late-endosomes and the endoplasmic reticulum (ER). The lipid transfer protein (LTP) STARD3 and STARD3NL, which are both anchored on the limiting membrane of late endosomes (LEs), interact with ER-anchored VAP [VAMP (vesicle-associated membrane protein)-associated protein] (VAP-A and VAP-B) proteins. This direct interaction allows ER–endosome contact formation. STARD3 or STARD3NL-mediated ER–endosome contacts, which affect endosome dynamics, are believed to be involved in cholesterol transport.

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STARD3: A Swiss Army Knife for Intracellular Cholesterol Transport

Contact ◽

10.1177/2515256419856730 ◽

2019 ◽

Vol 2 ◽

pp. 251525641985673

Author(s):

Laetitia Voilquin ◽

Massimo Lodi ◽

Thomas Di Mattia ◽

Marie-Pierre Chenard ◽

Carole Mathelin ◽

...

Keyword(s):

Lipid Transfer Protein ◽

Current Knowledge ◽

Cholesterol Transport ◽

Lipid Transfer ◽

Complex Process ◽

Associated Proteins ◽

Membrane Contacts ◽

Intracellular Cholesterol ◽

Domain 3 ◽

Steroidogenic Acute Regulatory

Intracellular cholesterol transport is a complex process involving specific carrier proteins. Cholesterol-binding proteins, such as the lipid transfer protein steroidogenic acute regulatory-related lipid transfer domain-3 (STARD3), are implicated in cholesterol movements between organelles. Indeed, STARD3 modulates intracellular cholesterol allocation by reducing it from the plasma membrane and favoring its passage from the endoplasmic reticulum (ER) to endosomes, where the protein is localized. STARD3 interacts with ER-anchored partners, notably vesicle-associated membrane protein-associated proteins (VAP-A and VAP-B) and motile sperm domain-containing 2 (MOSPD2), to create ER–endosome membrane contacts. Mechanistic studies showed that at ER–endosome contacts, STARD3 and VAP proteins build a molecular machine able to rapidly transfer cholesterol. This review presents the current knowledge on the molecular and cellular function of STARD3 in intracellular cholesterol traffic.

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Elevated Levels of StAR-Related Lipid Transfer Protein 3 Alter Cholesterol Balance and Adhesiveness of Breast Cancer Cells

American Journal Of Pathology ◽

10.1016/j.ajpath.2014.12.018 ◽

2015 ◽

Vol 185 (4) ◽

pp. 987-1000 ◽

Cited By ~ 28

Author(s):

Boris Vassilev ◽

Harri Sihto ◽

Shiqian Li ◽

Maarit Hölttä-Vuori ◽

Jaakko Ilola ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Lipid Transfer Protein ◽

Lipid Transfer ◽

Transfer Protein

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Anticancer Properties of Curcumin and Interactions With the Circadian Timing System

Integrative Cancer Therapies ◽

10.1177/1534735419889154 ◽

2019 ◽

Vol 18 ◽

pp. 153473541988915 ◽

Cited By ~ 2

Author(s):

Arpan De ◽

Dilshan H. Beligala ◽

Tyler M. Birkholz ◽

Michael E. Geusz

Keyword(s):

Cancer Cells ◽

Intracellular Signaling ◽

Antioxidant Properties ◽

Chemotherapeutic Agents ◽

Cancer Therapies ◽

Circadian Timing ◽

Intestinal Microbes ◽

Anticancer Properties ◽

Timing System ◽

Circadian Timing System

The phytochemical curcumin is a major component of turmeric. It has recognized activity against cancer cells and affects several intracellular signaling pathways. Many molecules targeted by curcumin also regulate the circadian timing system that has effects on carcinogenesis, tumor growth, and metastasis. Although the circadian clock within cells may be suppressed in tumors, cancer cells are subjected to daily hormonal and neural activity that should be considered when timing optimal curcumin treatments. Rapid curcumin degradation in blood and tissues provides a challenge to maintaining sustained levels suitable for inducing cancer cell death, increasing the need to identify when during the circadian cycle rhythmically expressed molecular targets are present. Curcumin is well tolerated by individuals ingesting it for possible cancer prevention or in combination with conventional cancer therapies, and it shows low toxicity toward noncancerous cells at low dosages. In contrast, curcumin is particularly effective against cancer stem cells, which are treatment-resistant, aggressive, and tumor-initiating. Although curcumin has poor bioavailability, more stable curcumin analogs retain the anti-inflammatory, antioxidant, antimitotic, and pro-apoptotic benefits of curcumin. Anticancer properties are also present in congeners of curcumin in turmeric and after curcumin reduction by intestinal microbes. Various commercial curcuminoid products are highly popular dietary supplements, but caution is warranted. Although antioxidant properties of curcumin may prevent carcinogenesis, studies suggest curcumin interferes with certain chemotherapeutic agents. This review delves into the complex network of curcuminoid effects to identify potential anticancer strategies that may work in concert with daily physiological cycles controlled by the circadian timing system.

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Friend or Foe: Hybrid proline-rich proteins determine how plants interact with and respond to beneficial and pathogenic microbes

10.1101/2021.08.26.457806 ◽

2021 ◽

Author(s):

Zeeshan Zahoor Banday ◽

Nicolas M Cecchini ◽

Allison T Scott ◽

Ciara T Hu ◽

Rachael C Filzen ◽

...

Keyword(s):

Pseudomonas Syringae ◽

Transmembrane Domain ◽

Lipid Transfer Protein ◽

Family Members ◽

Subcellular Location ◽

Protein Domain ◽

Lipid Transfer ◽

Growth Responses ◽

Signal Molecule ◽

Systemic Immunity

Plant plastids generate signals, including some derived from lipids, that need to be mobilized to effect signaling. We used informatics to discover potential plastid membrane proteins involved in microbial responses. Among these are proteins co-regulated with the systemic immunity component AZI1, a hybrid proline-rich protein (HyPRP) and HyPRP superfamily members. HyPRPs have a transmembrane domain, a proline-rich region (PRR) and a lipid transfer protein domain. The precise subcellular location(s) and function(s) is unknown for most HyPRP family members. As predicted by informatics, a subset of HyPRPs have a pool of protein that targets plastid outer envelope membranes (OEMs) via a mechanism that requires the PRR. Additionally, two HyPRPs may be associated with thylakoid membranes. Most of the plastid and non-plastid localized family members also have pools that localize to endoplasmic reticulum, plasma membrane or plasmodesmata. HyPRPs with plastid pools regulate, positively or negatively, systemic immunity against the pathogen Pseudomonas syringae. HyPRPs also regulate the interaction with the plant growth promoting rhizobacteria Pseudomonas simiae WCS417 in the roots to influence colonization, root system architecture and/or biomass. Thus, HyPRPs have broad and distinct roles in immune, development and growth responses to microbes and reside at sites that may facilitate signal molecule transport.

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