STARD3 and the identification of new cholesterol transport inhibitor [Tesi di dottorato]
Università degli Studi di Trieste, 2019-03-29

Although many advances in the cancer treatment have been made, the research is continuously searching new perspectives in order to provide the best possible outcome for all patients. An emerging challenge is the identification of new genes involved in cancer development and progression in order to develop novel therapeutic molecules to use alone or in combination with current therapies. In the last years, some research groups have focused their attention on a protein initially discovered to be overexpressed in breast cancer samples: the StAR-related lipid transfer domain-3 (STARD3). STARD3 is a member of a subfamily of lipid trafficking proteins characterized by a C-terminal steroidogenic acute regulatory domain (STARD), which shares a 35% of homology with the domain of StAR protein, STARD1, a transporter of cholesterol in mitochondria. They both belong to the START (steroidogenic acute regulatory protein–related lipid transfer) proteins family, involved in the non-vesicular transport of lipids in membranes. The crystal structure of the START domain of STARD3 revealed a hydrophobic cavity formed by the α/β helix grip structure of the 210 amino acids with which it binds one molecule of cholesterol at an equimolar ratio 1:1, transporting sterol from the endoplasmic reticulum (ER) to the endosomes. In human, it was demonstrated that STARD3 is overexpressed in different cancer cell lines and, in particular, in Her2 overexpressing breast cancer. In fact, STARD3 and HER2 are co-amplified and cooverexpressed in about 25% of breast cancers. The molecular mechanism by which STARD3 cooperates with others oncogene such as HER2 is still unclear. Nevertheless, STARD3 is implicated in therapy resistance of breast cancer, moreover, patients with a high level of STARD3 expression display metastasis, local recurrence and shorter overall survival. Recently, new evidences suggested a possible STARD3 overexpression also in colorectal, prostate and gastric cancers. Due to its involvement in cancer, STARD3 represents an attractive candidate as a target to cancer therapy and the identification of selective inhibitors is an undiscovered but interesting field of study. In collaboration with the University of Pisa that has developed the first pharmacophore-based virtual screening (VS) platform focuses on the identification of new inhibitors of the STARD3 mediated cholesterol transport, we carried out a study to identify a lead compound (VS1) endowed with an interesting activity, thus representing the first reported STARD3 inhibitor. The activity of the inhibitor was evaluated in breast and colorectal cancer cell lines by analyzing cell vitality and the level of focal adhesion kinase (FAK). Inhibition of STARD3 by VS1 results in a consistent reduction of cell vitality; additionally the activation of a specific STARD3 target (FAK) produced by the ligand, suggests a potent and specific activity of VS1 at cellular level.

diritti: none
In relazione con info:eu-repo/semantics/altIdentifier/hdl/11368/2942884
Settore BIO/12 - - Biochimica Clinica e Biologia Molecolare Clinica

Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD20019976