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A case study: nuclear receptors, vitamin D and cancer

A case study: nuclear receptors, vitamin D and cancer. A closer look at nuclear receptor function Vitamin D and its receptor A link to cancer? Tamoxifen , an anti-estrogen. An example for a family of transcription factors: Nuclear Receptors.

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A case study: nuclear receptors, vitamin D and cancer

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  1. A case study: nuclear receptors, vitamin D and cancer • A closer look at nuclear receptor function • Vitamin D and its receptor • A link to cancer? • Tamoxifen, an anti-estrogen

  2. An example for a family of transcription factors: Nuclear Receptors • found in all multicellular animals, absent in plants & fungi • 49 proteins in humans, 21 in Drosophila • bind steroid hormones, certain lipids and some other small lipophilic molecules • some nuclear receptors bind drugs and toxins • critical regulators of: • inflammation • maintaining salt concentrations • development • detoxification pathways • cholesterol homeostasis

  3. Nuclear Receptor pathways are “simple” and fast Nuclear Receptor pathway Conventional pathway

  4. Dimerization (strong) Transactivation (AF-2) NLS (ligand-dependent)

  5. Group I nuclear receptors reside in the cytoplasm when unliganded Ligand Nuclear Receptor (homodimer) Cytoplasmic retention protein

  6. Group II nuclear receptors are bound to DNA – even when unliganded

  7. Ligands for nuclear receptors: Links to development, metabolism and detoxification CAR PXR aka SXR

  8. Drug-Drug interactions occur through CYP3A4 CYP3A4 alone, a cytochrome P450 enzyme, is responsible for metabolizing 50-60% of all prescription drugs.

  9. Vitamin D: To good to be true? • A recent study showed that vitamin D intake reduces your personal risk of developing a range of cancers by 60%. In the study, patients received a daily dose of vitamin D in conjunction with calcium. Based on this and many other studies, the Canadian Cancer Society now recommends that Canadians take at least 1000 IU of Vitamin D per day.

  10. Taking out the first year of cancer cases results in 77% risk reduction

  11. What is Vitamin D? vitamin D is a STEROID PROHORMONE …and, once metabolized, a ligand for VDR

  12. Vitamin D3 Consequences of severe Vitamin D3 deficiency (“classic symptoms”) • Rickets (children) • Osteomalacia (adults): • “softening of the bone” • …due to reduced absorption of • calcium Risk factors for Vitamin D3 deficiency: Malnutrition pigmented skin Living in Canada and other Northern countries Obesity Advanced age

  13. Out of Africa models for human evolution Why did Northern Populations loose Skin Pigmentation?

  14. Estimated Vitamin D levels

  15. Relative cancer risk and vitamin D serum concentration

  16. Vitamin D supplementation prevents colon cancer in mice

  17. The Effect is specific to Vitamin D supplementation

  18. Vitamin D metabolism VDR VDR

  19. Anti-cancer pathways regulated by Vitamin D3

  20. Coming soon?: Nobel prize for nuclear receptor research

  21. Discovery of estrogen receptor and tamoxifen It was known that removing the ovaries of women with breast cancer would stop tumor growth in one out of three patients, however the molecular mechanism remained unknown Elwood V. Jensen and colleagues then showed that women with low expression levels of the Estrogen receptor did not respond to this treatment, establishing a screening procedure for breast cancer patients. The Jensen lab then developed a drug called tamoxifen, which mimics the effects of removing ovaries. Later it was shown that tamoxifen acts as an anti-estrogen and blocks the activity of the estrogen receptor in cancer cells.

  22. Tamoxifen competes with estrogen Estradiol Tamoxifen

  23. Tamoxifen acts as an anti-estrogen and prevents correct folding required for co-activator recruitment Estrogen Receptor bound to b-estradiol Estrogen Receptor bound to Tamoxifen

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