Virtually every pre-health student has to read a journal article at least once during his/her undergraduate years. Often, students find them intimidating, boring, or just plain dense. But these articles can also be incredibly fascinating, and they can be a great window into the research world.
One of the goals that I have with this website is to expose students to these journal articles by having our members post summaries of particular articles here.
Below is a summary that I wrote this past semester for one of my biology classes at Hunter.
The journal article can be found here.
In a 2005 scientific journal article entitled “Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer”, researchers at Stanford University School of Medicine describe the effects of calcitriol (the biologically active form of vitamin D that acts as a hormone) on tumorigenesis in the prostate. Their findings show that calcitriol affects the production of cyclooxygenase-2 (COX-2) and 15-prostaglandin dehydrogenase (15-PGDH), which are both involved in prostaglandin metabolism. Also, when paired with NSAIDS, calcitriol becomes an even more effective treatment in cancer.
Studies in the past have shown a possible link between prostate cancer and calcitriol. Prostate cancer is usually treated with radiation or surgery, and if it turns metastatic, it is treated with androgen blockers. However, blocking the production of androgens is only a temporary solution because the cancer goes from being androgen-dependent to androgen-independent, which is much harder to treat. Calcitriol has been shown to inhibit tumorigenesis in both types of prostate cancer, which is what makes it of such interest. Also, UV light is integral to the production of vitamin D in the body, and studies have shown that low levels of calcitriol in the body increase the risk of developing prostate cancer. Lastly, polymorphisms in the gene that encodes the vitamin D receptor may contribute to the development of this kind of cancer.
Two other points of interest are that 25-Hydroxyvitamin D3-1-α-hydroxylase, the enzyme that makes calcitriol in the kidney, and 24-Hydroxylase, the enzyme that helps catabolize calcitriol are both made in the prostate. Because the first enzyme converts 25(OH)D3 to calcitriol, it was thought that giving patients 25(OH)D3 could be an effective treatment, but it was discovered that cancer cells have low levels of 1-α-hydroxylase, and normal cells have high levels of the enzyme. Therefore, giving 25(OH)D3 wouldn’t be helpful to people who already have prostate cancer but would be helpful as a chemopreventative drug. 24-Hydroxylase is an enzyme that catabolizes calcitriol and is actually activated by calcitriol itself. In cells that are resistant to the anti-proliferative properties of calcitriol, there is a high level of this enzyme. However, when calcitriol is paired with a P450 inhibitor, then it’s effective against cancer in these types of cells.
At the time the article was written, the precise mechanism(s) behind the inhibitory effects of calcitriol on cancer cells were not known. However, the researchers cited evidence that calcitriol causes cell cycle arrest in the G1/G0 phase. “The growth arrest appears to be due to an increase in the expression of cyclin-dependent kinase inhibitors p21Waf/Cip1 and p27Kip1, a decrease in cyclin-dependent kinase 2 (Cdk2) activity, accompanied by a reduction in the nuclear fraction of this molecule and the hyperphosphorylation of the retinoblastoma protein (pRb)” (Moreno, et al). Calcitriol can also cause apoptosis of certain cells and decreases the expression of bcl-2, an anti-apoptotic gene. These are all effects that are commonly seen in anti-cancer agents.
The researchers did cDNA microarray analyses of normal cells and prostate cancer cells in order to find other molecular pathways. The analyses revealed that calcitriol is involved in the regulation of two genes involved in prostaglandin metabolism. It decreases the expression of COX-2, which is a gene that is involved in prostaglandin synthesis and increases the expression of 15-PGDH, which is a gene that is involved in the inactivation of prostaglandins. Studies have shown that prostaglandins play a role in the development of prostate cancer. Prostaglandins are made from arachidonic acid with the help of COX. COX-2 is activated by a host of molecules that are also involved in cancer including a host of mitogens and cytokines. Elevated levels of the enzyme have been shown to be present in multiple kinds of cancers. It’s been shown that high levels of COX-2 lead to the stabilization of survivin, which acts to block caspase activation, a key step in apoptosis. The mechanisms through which calcitriol decreases the expression of COX-2 were unknown at the time the article was published.
A second gene that calcitriol affects is 15-PGDH, which is involved in inactivating prostaglandins. The enzyme, 15-PGDH, inactivates prostaglandins by converting them to 15-keto derivatives. It has previously been shown that 15-PGDH is downregulated in colon cancer. This is because 15-PGDH expression is activated by TGFβ, and cancer cells have mutations in the TGFβ receptor. When 15-PGDF was transfected into these cancer cells, the tumors didn’t develop or were slowed down in their development. The researchers in this study show that calcitriol upregulates 15-PGDH in prostate cancer cells, which would prevent the accumulation of prostaglandins and the progression of the cancer.
Because calcitriol is involved in calcium homeostasis and bone metabolism, one side effect of excess calcitriol in the body is hypercalcemia. Scientists have tried to use calcitriol analogs as a substitute, and this has helped reduce side effects. However, towards the end of the article, the researchers suggest that another way to mediate side effects and to more effectively repress tumorigenesis is to use calcitriol with NSAIDS. NSAIDS have been shown to suppress the development of prostate cancer as well as other kinds of cancers. They do this by inhibiting both COX-1 and COX-2. However, NSAIDS have cardiovascular side effects, which can be life- threatening. If calcitriol and NSAIDS are used together, then lower concentrations of both drugs can be used, and the risk of hypercalcemia and cardiovascular issues would be reduced. Since calcitriol affects the expression of COX-2, lower levels of the enzyme will be made in the body so lower levels of NSAIDS will be needed to counteract COX-2.
Overall, this article gives a thorough overview of the current knowledge of how calcitriol impacts cancer cells as well adding in new experimental material that shows the link between calcitriol and prostaglandin metabolism. What’s most exciting about this link is that calcitriol is naturally synthesized by the body so giving patients more calcitriol would result in less side effects than giving them other types of treatment. Also, the researchers’ suggestion of using calcitriol in conjunction with NSAIDS seems like an effective combination that would produce good results with few side effects.
Moreno, J., Krishnan, A. V., & Feldman, D. (2005). Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer. The Journal of steroid biochemistry and molecular biology, 97(1), 31-36.