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Urology Research Laboratory
Harrison Department of Surgical Research
Dr. Samuel K. Chacko
 
Urologic Oncology Research
 

The broad theme of research in Dr. Malkowicz’s and Dr. Fredericks’ laboratory is to elaborate mechanisms of progression of urological cancers in order to discover potentially new avenues for therapy. We continue to focus on the relevance of the TERE1 tumor suppressor protein to understand how it represents a liability to invasive tumor cell metabolism and growth.

Tumor Suppression: We originally defined a tumor suppressor role for the TERE1 protein based on reduced expression in invasive bladder and prostate cancer specimens and the dramatic inhibition of tumorigenic growth of bladder cancer cell lines upon ectopic expression. A role in cholesterol homeostasis and metabolism was suggested by TERE1 binding to APOE, a cholesterol and triglyceride carrier, and to TBL2, a candidate protein in triglyceride disorders. This view of TERE1 was reinforced by the recognition of the cholesterol binding CRAC motif, and natural mutations in Schnyder’s Corneal Dystrophy, a rare disease of cholesterol and lipid accumulation. Our research has focused on cholesterol as a determinant of tumor progression.

Cholesterol and Tumor Progression: As an essential component for cell membranes required for tumor cell proliferation, and as an integral modulator of membrane signaling complexes for growth, oxidative stress, and apoptosis, elevated cholesterol has potential for simultaneously affecting multiple facets of tumor progression. In prostate and breast cancer elevated cholesterol serves as a precursor to steroid metabolism and intracrine growth mechanisms causing progression. In renal, liver, colon, head and neck, melanoma, and other non-hormone dependent cancers, diverse mechanisms link intracellular cholesterol and tumor progression. We currently study the role of TERE1 and associated proteins in cholesterol modulation in bladder, prostate, and renal cancers, in which reduced TERE1 levels are associated with progression.

TERE1/TBL2: Novel cholesterol-modulating mitochondrial proteins: Altering the dosage of TERE1 and TBL2 mitochondrial proteins in bladder, prostate cancer cells and transformed kidney cells can inversely modulate cellular cholesterol from 20-50%. Natural point mutations in TERE1 affect the interaction with APOE and alter cell cholesterol levels, hence, may be a basis for lipid accumulation in Schynder’s Corneal Dystrophy. These mutations also affect binding to TBL2. TBL2 is implicated in triglyceride disorders, TGF? and ATM/ATR stress signaling, yet its function is unknown. We have co-localized TERE1 with TBL2 in mitochondria and we are examining its role in oxidative stress signaling, currently recognized as a driving force in tumor metastasis.

Vitamin D, cholesterol and steroiodogenesis: The presence of VDRE’s within the TERE1 promoter, and the inhibitory effects of 1,25-OH vitamin D3 on LnCaP cell growth, have led us to examine the inducibility of TERE1 expression and effects on cholesterol in LnCaP prostate cancer cell clones by 1,25-OH vitamin D3 and MART-10 analogs. Over-expression of TERE1 reduces cell cholesterol. In accord with knock down of TERE1 expression and elevated cholesterol levels, the steroidogenic LnCaP C81 cells exhibit a reduced TERE1 expression and an elevated cholesterol level and synthesis. This is consistent with a contribution of TERE1-expression loss to castrate-resistant prostate cancer progression.

Mitochondrial to nuclear signaling defect: Recently, TERE1 (aka. UBIAD1) was shown to contribute to synthesis of menaquinone, which provides a unifying hypothesis to explain our observations regarding TERE1-mediated tumor suppression and cholesterol modulation. Menaquinone is known to inhibit over a dozen different types of tumor cell lines via redox cycling, oxidative stress, thiol arylation, and mitochondrial damage. Menaquinone is also a ligand for SXR nuclear receptor signaling, previously shown to activate LXR cholesterol efflux mechanisms. In addition to cholesterol depletion, SXR and LXR are implicated in several mechanisms leading to androgen deprivation and prostate cancer inhibition. The loss of TERE1 expression appears to be a mitochondrial to nuclear signaling adaptation that invasive tumor cells acquire to uncouple oxidative stress signaling in mitochondria from apoptosis and growth inhibition and by elevation of cholesterol, drive intracrine growth during tumor progression.

 
Submitted Abstracts
  1. The TERE1 (UBIAD1) Protrain Reduces Cholesterol in C81-LnCaP Prostate Cancer Cells Induction by 1,25-OH Vitamin D3 or Ectopic Expression (PDF)
  2. Ectopic TERE1 (UBIAD1) Expression Induces Oxidative Stress and AKT Activation in Bladder Cancer Cells (PDF)
  3. The LIM Protein LIMD2 Functions as a Biomarker for Metastasis in Multiple Tumor Types (PDF)

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