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Cancer

Vitamin D Stops Cancer Growth by Activating NAD⁺ and Sirtuin-1: Research from Spain

Vitamin D reduces human colorectal cancer cell growth by activating the NAD+ dependent enzyme sirtuin-1.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • Vitamin D increases the longevity-associated enzyme sirtuin-1 (SIRT1) in human colorectal cancer cells. 
  • NAD+ levels and the NAD+ dependent activity of SIRT1 are elevated in response to vitamin D. 
  • The anti-cancer effects of vitamin D are mediated by SIRT1 activity.  

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide, expected to increase by 60% around 2030. While previous studies have suggested vitamin D deficiency is a risk factor for colon cancer, researchers from the University of Rey Juan Carlos in Spain shed light on how this is possible.  

In the journal eLife, García-Martínez and colleagues show that vitamin D increases SIRT1 levels in human CRC cells. They go on to show that vitamin D increases NAD+ levels and the NAD+ dependent activity of SIRT1. Furthermore, the researchers reveal that the anti-cancer effects of vitamin D are mediated by SIRT1. 

Vitamin D and SIRT1 Reduce Cancer Cell Proliferation 

To shed light on how vitamin D could stop the spread of CRC, García-Martínez and colleagues examined CRC cells donated from one male and one female CRC patient. They then treated the CRC cells with calcitriol (a.k.a. 1,25(OH)2D3) — the molecule vitamin D becomes once it is metabolized by our body. 

In the CRC cells, SIRT1 protein and mRNA levels doubled in response to calcitriol. Further experiments showed that this increase in SIRT1 was mediated by the vitamin D receptor, which calcitriol binds to exert its effects on cells. These findings suggest that vitamin D increases SIRT1 in CRC cells by binding to the vitamin D receptor.

 Vitamin D Enhances SIRT1 Levels in Colorectal Cancer Cells. In both male (HCT 116) and female (HT-29) colorectal cancer cells, SIRT1 levels (SIRT1/TBP) double following exposure to calcitriol (1,25(OH)2D3), the active metabolite of vitamin D.
(García-Martínez et al., 2023 | eLife) Vitamin D Increases SIRT1 Levels. In male (HCT 116) and female (HT-29) colorectal cancer cells, SIRT1 levels (SIRT1/TBP) double in response to the active metabolite of vitamin D, calcitriol (1,25(OH)2D3).

The function of SIRT1 is to remove chemical tags called acetyls from proteins. In doing so, SIRT1 promotes efficient energy utilization and protects cells from environmental challenges. In contrast, the dysregulation of SIRT1 accelerates age-related diseases like diabetes and cancer. Furthermore, SIRT1 uses NAD+ as fuel in order to function. 

For this reason, García-Martínez and colleagues measured NAD+ levels in calcitriol-treated CRC cells. They also measured how well SIRT1 removes acetyls from proteins, a process called deacetylation. The results showed that calcitriol treatment doubled NAD+ levels and increased NAD+ dependent deacetylase activity 1.5-fold.

 Vitamin D Enhances NAD+ Levels and SIRT1 Function. Calcitriol (1,25(OH)2D3), the active metabolite of vitamin D, doubles NAD+ levels and boosts SIRT1 function (Relative NAD+ dependent deacetylase activity) in both female (HT-29) and male (HCT 116) colorectal cancer cells.
(García-Martínez et al., 2023 | eLife) Vitamin D Increases NAD+ and NAD+ Dependent SIRT1 Function. In female (HT-29) and male (HCT 116) colorectal cancer cells, the active metabolite of vitamin D, calcitriol (1,25(OH)2D3) increased SIRT1 function (Relative NAD+ dependent deacetylase activity) and doubled NAD+ levels. 

To determine how vitamin D could slow cancer growth, García-Martínez and colleagues measured the proliferation of CRC cells in a dish (in vitro). They also measured CRC proliferation in response to calcitriol, or an activator of SIRT1 called SRT1720. 

The researchers found that both calcitriol and SRT1720 strongly reduced CRC cell proliferation. These findings suggest that vitamin D can counter cancer growth by activating SIRT1. Furthermore, directly activating SIRT1 can also counter cancer cell proliferation. 

Vitamin D and SIRT1 Activation Suppress Cancer Cell Growth. Calcitriol (1,25(OH)2D3), the active form of vitamin D, and SRT1720, a SIRT1 activator, equally inhibit the proliferation of male (HCT 116) colorectal cancer cells.
(García-Martínez et al., 2023 | eLife) Vitamin D & SIRT1 Activation Reduces Cancer Cell Growth. The active metabolite of vitamin D, calcitriol (1,25(OH)2D3) and the SIRT1 activator SRT1720 equally reduce the proliferation of male (HCT 116) colorectal cancer cells.

Activating SIRT1 to Counter Cancer 

The findings of García-Martínez and colleagues imply that vitamin D and other SIRT1 activators can protect against multiple types of cancer, including CRC. The authors conclude, 

“The multilevel activation of SIRT1 deacetylase by 1,25(OH)2D3 broadens the range of known 1,25(OH)2D3 targets and positions SIRT1 as an important mediator of the protective action of vitamin D against CRC and potentially other neoplasias and non-tumoral diseases.”

While synthetic SIRT1 activators like SRT1720 are not yet available to consumers, there are several plant-based molecules that have been shown to activate SIRT1: 

Because it may be challenging to consume therapeutic doses of plant-based SIRT1 activators via diet, supplementation is an option. SIRT1 can also be activated by caloric restriction — reducing daily caloric intake — and fasting. Furthermore, regular exercise promotes adaptive responses that normalize SIRT1 levels in multiple tissues. Therefore it may be possible to mitigate cancer growth with a healthy diet and consistent exercise.

Source

García-Martínez JM, Chocarro-Calvo A, Martínez-Useros J, Fernández-Aceñero MJ, Fiuza MC, Cáceres-Rentero J, De la Vieja A, Barbáchano A, Muñoz A, Larriba MJ, García Jiménez C. Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer. Elife. 2023 Aug 2;12:RP86913. doi: 10.7554/eLife.86913. PMID: 37530744; PMCID: PMC10396337.

References

Iside, C., Scafuro, M., Nebbioso, A., & Altucci, L. (2020). SIRT1 Activation by Natural Phytochemicals: An Overview. Frontiers in Pharmacology, 11, 551744. https://doi.org/10.3389/fphar.2020.01225

DiNicolantonio JJ, McCarty MF, O’Keefe JHNutraceutical activation of Sirt1: a reviewOpen Heart 2022;9:e002171. doi: 10.1136/openhrt-2022-002171

Radak, Z., Suzuki, K., Posa, A., Petrovszky, Z., Koltai, E., & Boldogh, I. (2020). The systemic role of SIRT1 in exercise mediated adaptation. Redox Biology, 35, 101467. https://doi.org/10.1016/j.redox.2020.101467

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