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STAT

An MUSC blog
Keyword: prostate cancer

Vitamin D Illustration

Summary: Investigators at the Medical University of South Carolina and Ralph H. Johnson VA Medical Center report clinical research showing that African-American and European-American men with prostate cancer exhibit significantly different expression of genes associated with immune response and inflammation, in the July 2016 issue of  Pharmacogenomics. Systems-level, RNA analyses support the concept that inflammatory processes may contribute to racial disparities in disease progression and that vitamin D3 supplementation can modulate pro-inflammatory transcripts.

The results of clinical studies by investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center (VAMC), reported in the July 2016 issue of Pharmacogenomics (doi:10.2217/pgs-2016-0025) , demonstrate transcriptome-level linkages between racial disparities in circulating levels of vitamin D and expression of pro-inflammatory genes in African American (AA) patients with prostate cancer compared to European American (EA) patients.

Racial disparities in prostate cancer are well documented with AA men having significantly higher risk of developing prostate cancer and significantly higher mortality rates than EA men. In addition, among patients presenting at the same disease stage, AA men often have higher prostate-specific antigen (PSA) levels and higher-grade tumors than EA men. However, the biological mechanisms underlying these substantial and persistent disparities are unclear.

Researchers at MUSC and VAMC noticed that racial disparities in prostate cancer mirror differences in circulating levels of vitamin D between AA and EA patients. Vitamin D3 is known to have multiple anti-cancer actions including suppression of cyclo-oxygenase-II (an independent predictor of cancer recurrence) and inhibition of IL-8 (an angiogenic, pro-inflammatory cytokine). Prostate cells express the vitamin D receptor, vitamin D-25-hydroxylase, 25 hydroxyvitamin D-1-alpha-hydroxylase, and 25-hydroxyvitamin D-24-hydroxylase. Thus, normal prostate cells can synthesize 25(OH)D3 (calcidiol) from vitamin D (cholecalciferol), and 1,25(OH)2D3 (calcitriol) from 25(OH)D3. 1,25(OH)2 D3 (calcitriol) is the bioactive, hormonal, and most potent form of vitamin D and facilitates cell-to-cell communication via paracrine/autocrine pathways.

Sebastiano Gattoni-Celli, M.D., Professor of Radiation Oncology at MUSC, and senior author on the article, explains how his team came to explore the therapeutic potential of vitamin D supplementation in prostate cancer, "A lot of previous work shows that D3 levels are much lower in African Americans than in European Americans and it's well established that prostate cells are very sensitive to vitamin D levels. So this raised the possibility that long-term vitamin D deficiency may contribute to the progression of prostate cancer, especially among African American men. We began to wonder whether eliminating racial disparities in circulating levels of vitamin D, through supplementation, could help reduce the disparities we see in prostate cancer outcomes."

The team designed a prospective, placebo-controlled, clinical study to investigate the effects of a daily 4,000 IU vitamin D3 supplementation over a two-month period among 27 men (10=AA, 17=EA) who had elected to treat their prostate cancer via prostatectomy. A trial length of two months was chosen to leverage the recommended, standard-of-care recovery period between their biopsy and surgery procedures. Using high-throughput RNA sequencing, they performed a series of genome-wide expression profiling experiments to generate transcriptional profiles of patients' prostate tissue samples and assessed them using systems-level analyses. Their primary aims were to: (1) illuminate any molecular differences in gene expression that may be related to prostate cancer disparities between AA and EA men; and (2) investigate any effects vitamin D supplementation may have on the prostate transcriptome.

Not only did the team find significant differences in gene expression between AA and EA men but also between AA men receiving vitamin D supplements and AA men receiving placebo. Due to the size of the RNA sequencing dataset, results are reported as adjusted p-values (or q-values) which represent the smallest 'false discovery rate' at which a result can be called significant. A total of 3,107 prostate genes were differentially expressed between the AA and EA groups (q<0.1) with 8,238 differentially expressed transcripts between AA and EA subjects (q<0.4). Analyses of these found that AA study patients had substantially elevated expression of transcripts related to immune response and inflammation.

"The number of genes expressed differently in AA and EA was a really big surprise—we found differences in over 8,000 genes,” said Gattoni-Celli. “I expected something but not this massive difference and it was not a fluke. When we compared our results with previous studies using a less advanced technology, we saw that they, too, found these differences, but not as many.”

“Our findings captured all of the differences observed in previous studies but also many more because newer RNAseq technology and Big Data analytical approaches allowed us to see the transcriptome in greater detail,” noted Gary Hardiman, Ph.D., Professor of Medicine and Public Health Sciences and Bioinformatics Director for the Center for Genomic Medicine at MUSC, and co-senior author on the article. “This analysis was performed using the OnRamp BioInformatics Genomics Research Platform we deployed at MUSC a little over a year ago. Our approach converged advanced genomics analysis, comprehensive data management, big data analytics and hyperscale servers. A ‘Big Data’ analytical pipeline that utilized Hadoop software was implemented. This enabled an automated RNAseq workflow to process the patient data and explore differential prostate gene expression analysis between AA and EA men and sensitively interrogate the effects of vitamin D supplementation with robust statistical power.”

When comparing AA men receiving vitamin D supplementation to AA men receiving placebo,  the team found 817 differentially expressed genes (q<0.4). However, no similar difference in gene expression was observed between EA men receiving vitamin D supplementation versus placebo. Comparing the 8,238 differentially expressed transcripts between AA and EA subjects with the 817 genes that were differentially expressed among AA men receiving vitamin D supplementation and AA men receiving placebo, the team found an overlap of 346 genes. This finding suggests that a substantial number of genes that are differentially expressed across racial groups can be affected by a brief (2-month) course of vitamin D3 supplementation in AA patients.

This research is an important step in understanding the molecular underpinnings of health disparities in prostate cancer. Further clarification of race-based transcriptome differences and the role of vitamin D in prostate tissue may lead to use of vitamin D3 supplementation as an early-stage therapeutic option in prostate cancer. Furthermore, results from studies among AA and EA women with breast cancer could extend these findings because breast cancer, like prostate cancer, is an endocrine cancer, with many similarities including sensitivity to vitamin D.

An accompanying editorial by Batai K and Kittles RA, "Can vitamin D supplementation reduce prostate cancer disparities?" was published in the same issue of Pharmacogenomics (volume 17, number 11, 2016, pages 1117-1120).   

Accumulation of DihydroceramidesSummary: Sphingosine kinase inhibitors are a new category of drugs that act on specific enzymes involved in sphingolipid metabolism to reduce the formation of a pro-cancer, pro-inflammatory lipid signaling molecule known as sphingosine-1 phosphate (S1P). Preclinical studies led by immunologist Christina Voelkel-Johnson, Ph.D., of the Medical University of South Carolina showed that a first-in-class sphingosine kinase 2 inhibitor slowed growth of aggressive prostate cancer cells.

A first-in-class sphingosine kinase 2 inhibitor slowed the growth of castration-resistant prostate cancer cells, in part by inhibiting the enzyme dihydroceramide desaturase (DEGS), but did not kill them, according to the results of preclinical in vitro and in vivo studies published in the December 2015 issue of Molecular Cancer Therapeutics by researchers at the Medical University of South Carolina (MUSC) and others.

Christina Voelkel-Johnson, Ph.D., Associate Professor of Microbiology and Immunology at MUSC, led the study, which was funded by a pilot grant from MUSC Hollings Cancer Center. Co-authors include Charles D. Smith, Ph.D., who developed the compound and led an earlier phase 1 trial at MUSC Hollings Cancer Center; oncologist Michael Lilly, M.D., a prostate cancer specialist; and Richard Drake, Ph.D., director of the Proteomics Core at MUSC, who has developed techniques to use MALDI imaging mass spectrometry to measure sphingolipid levels.

Sphingosine kinase inhibitors are a new category of drugs that reduce the generation of sphingosine-1-phosphate. This lipid signaling molecule promotes cancer cell growth and survival, thereby supporting the development of resistance to chemotherapy and radiation by cancer cells.

The study reported in Molecular Cancer Therapeutics showed that the compound YELIVA™ (ABC294640; RedHill Biopharma Ltd.; Tel Aviv, Israel) slowed prostate cancer cell proliferation by inhibiting sphingosine kinase 2, but also that it did something unexpected. “By inhibiting a second sphingolipid enzyme (DEGS), the compound increases levels of another class of lipids - dihydroceramides - which may contribute to the growth suppressive effects of the drug,” says Voelkel-Johnson. This study is the first to show activity for this compound against DEGS and to potentially link inhibition of DEGS to slowing the growth of castration-resistant prostate cancer cells. Treatment with YELIVA™ (ABC294640) increased dihydroceramide levels even in the absence of sphingosine kinase 2. 

The MUSC team conducted both in vitro and in vivo studies with YELIVA™ (ABC294640) in castration-resistant prostate cancer, relying on the MUSC Lipidomics Shared Resource for measurement of sphingolipid levels and the MUSC Proteomics Center for MALDI imaging mass spectrometry.

 In vitro studies conducted with castration-resistant mouse prostate cancer cells (TRAMP-C2) showed that treatment with YELIVA™ (ABC294640) reduced expression of the androgen receptor and the oncogene c-Myc, both important therapeutic targets for prostate cancer. Although many existing prostate cancer therapies target the androgen receptor, none directly target c-Myc.

To test in vivo response, one million TRAMP-C2 cells were injected under the skin of mice with an intact immune system, which were then treated with YELIVA™ (ABC294640) three days later. MALDI imaging mass spectrometry showed the presence of YELIVA™ (ABC294640) within murine tumors and confirmed in vitro findings of increased dihydroceramide levels.

“The significance of these findings is that this compound might be a novel therapeutic for advanced prostate cancer,” says Voelkel-Johnson, who believes that combination regimens of YELIVA™ (ABC294640) and focal radiation in this difficult-to-treat patient population deserve further study.

See full EurekAlert! release at http://www.eurekalert.org/pub_releases/2016-01/muos-anc012816.php

Image Caption:

The signal for ABC294640 is detected only when the drug but not the vehicle was administered (upper panel). The intensity for two different dihydroceramides is shown in the middle panel (dhC16-cer) and lower panel (dhC18-cer). A color bar indicates the signal intensity. Adapted with permission from the American Association for Cancer Research : Venant H, et al. The Sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides In vitro and In vivo. Molecular Cancer Therapeutics; 2015 Dec; 14(12):2744-52. doi: 10.1158/1535-7163.MCT-15-0279.

photo of a box of fruits and vegetablesA recent study led by MUSC professor David P. Turner, Ph.D. finds that lifestyle habits such as diet and exercise could affect the progression of cancer and the rate of survival, but so could race. According to the study published in Cancer Research in May, our bodies have to metabolize food to obtain the sugars we need, thus leaving behind a reactive-metabolite waste product. These leftovers are referred to as advanced glycation end-products (AGE), and this study addresses the apparent correlation between AGE levels and the prevalence of age-related diseases among non-Hispanic whites and African Americans. 

High levels of AGE are associated with diabetes, cardiovascular disease, Alzheimer’s, and cancer. These levels are highest in African American men with prostate cancer—they are 1.5 times more likely to be diagnosed with this cancer and twice as likely to die from it than non-Hispanic whites. Consumption of sugar and processed food can contribute to AGE levels. Food preparation (i.e., browning) also plays a large role in these levels. They are higher in the West, where the diet commonly consists of red meat, refined grains, and high sugar and fatty foods.

 When analyzing serum from cancer patients, Turner found that AGE levels were significantly higher in patients with cancer than those without. Breast and prostate immortalized cancer cell lines grew more, migrated farther, and invaded more when treated with AGE. In conjunction with higher AGE levels, African Americans have more C-reactive protein (CRP), making them more susceptible to chronic inflammation. Chronic inflammation is one of the key factors implicated in the development of cancer, along with oxidative stress, an increased immune response, and the presence of AGE.

AGE cannot be completely eliminated, but levels of circulating AGE can be lowered. Simply changing lifestyle habits can slow down the accumulation of AGE in the body. Avoid food with high protein, sugar, and fat, as well as processed foods. Then increase your intake of natural grains, fruits, and vegetables. Change the way you prepare your food by cooking meats at a lower temperature for a longer period of time, skipping the browning step of a dish. You can also replace high-sugar, oil-based marinades with lemon juice, vinegar, and tomato juice. The last big step of lowering your AGE levels is exercise. A sedentary lifestyle only allows for more AGE to accumulate.

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