LINUS PAULING INSTITUTE SPRING/SUMMER 2005 RESEARCH REPORT

Emily HoMichelle Yan

Zinc and Prostate Cancer

Emily Ho, Ph.D., LPI Principal Investigator
Michelle Yan, OSU Graduate Student

Summary: Although zinc is an essential mineral in human nutrition, many people have insufficient zinc status due to low dietary intake. Zinc functions as an antioxidant and is involved in many critical biochemical reactions. It also helps to protect DNA from damage and assists in its repair. Zinc is especially important in the prostate and may protect it from early damage that could lead to cancer, although our studies with prostate cancer cells in culture indicate that zinc supplementation may be less useful in treating prostate cancer.

The role of zinc in a wide range of cellular processes, including cell division and proliferation, immune function, and defense against free radicals, has been well established. Zinc is the most abundant trace element in cells, and increasing evidence emphasizes zinc’s important role in both genetic stability and function. For example, about 25% of the total zinc present in rat liver is found within the nuclei of cells, which also contain the DNA. Zinc is a component of chromatin, which is the stable complex of DNA and proteins in the cell’s nucleus, and also plays a role in DNA replication, transcription, and repair. Zinc is found in over 300 enzymes, including copper/zinc superoxide dismutase, which is an important antioxidant enzyme, and in several proteins involved in DNA repair. Zinc also helps to protect cellular components from oxidation and damage. Our laboratory is investigating the links between zinc deficiency, oxidative stress, DNA damage and repair, and the risk of cancer.

Zinc deficiency can lead to immune dysfunction and impairments in growth, cognitive function, and hormonal function. It is estimated that nutritional zinc deficiency affects over 2 billion people worldwide, especially those in developing countries. However, deficiency is not a problem only in developing countries. According to the USDA’s 1996 Continuing Survey of Food Intakes, over 70% of Americans do not consume the recommended daily allowance for zinc, which is 8 mg for women and 11 mg for men. Although severe zinc deficiency is rare, 10% of individuals do not consume even half of the RDA for zinc, indicating that a significant percentage of the population may be marginally zinc deficient. The pathological signs of zinc deficiency include stunted growth, impaired childbirth, neuropathy, decreased appetite, diarrhea, dermatitis, hair loss, bleeding, hypotension, and hypothermia. Zinc deficiency affects many biological systems because of zinc’s essential role in many aspects of cellular metabolism. Zinc deficiency can occur in populations with low dietary zinc intake and high intake of phytate, a substance found in seeds and cereal grains that binds strongly to zinc, making it biologically unavailable. Populations that are at high risk include infants and young children, whose requirements for zinc are high. In addition, the elderly have an increased risk of zinc deficiency because zinc absorption may become impaired with age. The elderly also tend to consume low-zinc diets. Foods rich in zinc include red meat, seafood, and several plant sources, such as whole grains and legumes, but the zinc in plant foods is much less bioavailable.

The role of zinc in cancer has received increasing attention for several reasons. The link between zinc deficiency and cancer has now been established by human, animal, and cell culture studies. We also know that zinc status is compromised in cancer patients compared to healthy people. Oxidative DNA damage and chromosome breaks have been reported in animals fed a zinc-deficient diet. In rats, dietary zinc deficiency causes an increased susceptibility to tumor development when the rats are exposed to carcinogens.

Zinc also appears to play an important role in maintaining prostate health, but the precise function of zinc in the prostate is unknown. We are especially interested in how zinc deficiency or supplementation may influence the development of prostate cancer. Prostate cancer is the second leading cause of cancer deaths in American men, and most elderly men have some abnormal prostate cells. Still, the cause of prostate cancer is unclear. Some of the risk factors include family history, age, and diet. The normal human prostate accumulates the highest level of zinc of any soft tissue in the body, but we don’t know why. However, cancerous prostates have much less zinc than normal prostates, and several studies have implicated impaired zinc status in the development and progression of prostate malignancy. There is also some evidence that increased dietary zinc is associated with a decrease in the incidence of prostate cancer. We have shown in various cell types that changes in intracellular zinc dramatically affects DNA damage and repair, and, hence, the risk of cancer. It is possible that dietary zinc deficiency will increase a man’s risk for oxidative DNA damage in prostate cells. Zinc supplementation strategies may not only aid in the prevention of cancer, but could also play an important role in limiting its malignancy. As an antioxidant and a component of many DNA repair proteins, zinc plays an important role in protecting DNA from damage. Zinc also functions as an anti-inflammatory agent and can promote programmed cell death, or apoptosis. Thus, zinc supplementation has the potential to target multiple points of the carcinogenesis cascade.

The efficacy of zinc supplements in preventing prostate cancer is controversial. Although several studies have shown that high cellular zinc levels inhibit prostate cancer cell growth, a recent epidemiological study showed an increased risk for prostate cancer in men who took high-dose zinc supplements. Increased cancer risk was seen with very high-dose (over 100 mg/day) or long-term (more than 10 years) zinc supplement use. The current tolerable upper intake level for zinc is 40 mg/day, established by the U.S. Institute of Medicine. Thus, it is possible that the subjects in the epidemiological study could have been in the toxic range of zinc intake. As with most therapeutics, higher doses do not always equate with an increase in efficacy.

The goal of our studies was to identify the mechanisms by which zinc can affect prostate health and the development of prostate cancer. We hypothesize that zinc functions to protect the prostate from oxidative damage and maintains DNA integrity in prostate epithelial cells. We also propose that zinc supplementation will be beneficial in decreasing susceptibility to prostate cancer by protecting from oxidative damage, enhancing DNA repair, and limiting uncontrolled cell proliferation.

There are two distinct phases of prostate cancer development. In its early stages, prostate cancer is hormone dependent, requiring the male hormone androgen to grow. As the cancer progresses, it becomes androgen independent, no longer requiring androgens to grow. Due to the two distinct phases of prostate cancer, we used both early- and late-stage human prostate cancer cell lines in our research. In addition, we examined benign prostate hyperplasia cells. Although these cells are not necessarily pre-cancerous cells, they represent a stage of increased growth. We compared the cancer and hyperplasia cells to normal prostate cells. These four cell types helped us to determine at what stage of carcinogenesis zinc would be most beneficial and how zinc levels affect prostate cancer development.

Zinc treatmentWe treated late-stage androgen-independent prostate cancer cells, early-stage androgen-dependent prostate cancer cells, and benign prostate hyperplasia cells with doses of zinc ranging over five-fold concentrations. We then examined the growth and viability of these cells (see graph). Surprisingly, zinc had little effect on the viability of the prostate cancer cells, but even low zinc treatments resulted in a marked decrease in cell viability of the benign prostate hyperplasia cells. A similar response pattern was seen when cell growth was examined after zinc treatment.

We next examined molecular changes in the benign prostate hyperplasia cells treated with zinc. These experiments revealed that zinc induced programmed cell death, or apoptosis, in these cells.

To examine the effect of zinc deficiency, we grew normal prostate epithelial cells in either zinc-deficient or zinc-adequate growth medium. Zinc deficiency induced single strand DNA breaks and oxidative stress in the normal prostate epithelial cells. To better understand the mechanisms by which zinc deficiency may cause damage, we examined changes in gene expression using microarray analysis. Since zinc deficiency increases oxidative stress and DNA damage, we expected genes involved in DNA repair to be upregulated due to zinc deficiency. However, initial analysis did not find any changes in the expression of genes associated with DNA repair. Although this result is surprising, it may indicate that zinc deficiency impairs the ability of these cells to respond to DNA damage by increasing DNA repair. Other genes related to oxidative stress and cell proliferation were also affected by zinc deficiency.

Overall, our research suggests that zinc supplementation may be more helpful in the early stages of cancer development rather than as cancer treatment. Of course, our results are limited to human cells in culture. Additionally, zinc deficiency in normal prostate epithelial cells not only induces DNA damage itself, but also may impair the cell’s ability to respond to DNA damage, increasing the risk of prostate cancer development. Adequate zinc levels are essential for maintaining healthy prostate cells, but zinc supplementation may not prevent already cancerous prostate cells from growing.

Our future studies will explore the effects of both zinc deficiency and supplementation on the development of prostate tumors in animals. We also plan to examine associations between dietary zinc status and the risk of prostate cancer in people. These studies will help to define the role of zinc in maintaining prostate health.

Last updated May, 2005


Micronutrient Research for Optimum Health


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