Category Archives: cancer

Don’t Stress – Just ASK!: New Role Found for Stress-Activated Molecule in Preventing Cellular Dustbins from Degrading Waste

The stress-activated molecule, ASK, prevents cellular dustbins from degrading waste proteins and may offer a new target for treating various diseases including cancer, AIDs and neurodegenerative diseases, according to a study in the Journal of Biological Chemistry this month.

It happens to us all, you’ve got a ridiculously tight deadline, an exam tomorrow, or something else that really stresses you out, and your heart starts beating a little bit faster, your palms get sweaty, and you feel sick. These responses are some of the direct results of stress on the human body. Similarly, just as the body as a whole can react to stress, so can individual cells.

ASK1 is triggered when a cell is exposed to stressful stimuli including oxidative stress (when toxic free radicals are produced within the cell which can cause serious damage to DNA) or endoplasmic reticulum stress (accumulation of unwanted proteins within the endoplasmic reticulum [the area of the cell responsible for protein production]). When triggered, ASK1 translates the stimuli of stress to within the cell, activating various intracellular processes linked to cell death and normal cell function. However, recent research by Um and Im in the November issue of the Journal of Biological Chemistry have found an additional role for ASK1 in that it inhibits the actions of cellular dustbins, or ‘proteasomes’, which eat up unwanted proteins in cells, a process which is vital for normal cell function.

Proteasomes break down unwanted proteins by a process called proteolysis to smaller components called amino acids, which are then re-used to make more new proteins. These unwanted proteins are tagged by a small protein called ubiquitin. Once tagged, these proteins are doomed as the cell is alerted to add additional ubiquitin molecules, and degrade the tagged protein. Well, that’s the norm, but as with most diseases sometimes something goes wrong and proteasomes  can malfunction. As a result, some proteins essential for normal cell function, are lost or accumulated depending on whether protein degradation is increased or decreased. This can lead to diseases such as cancer, AIDS, and neurodegenerative diseases .

In a series of elaborate and very thorough experiments, Um and Im investigated the link between ASK1 and proteasome function (these guys were meticulous; in fact Tefalhead reckons the whole set of experiments took 2 to 3 years!).

They specifically chose to work on the 26S proteasome, the most common proteasome in human cells, which is composed of two 19S ‘lids’ where the proteins are tagged for destruction and the 20S hollow core where proteins are mashed up (Figure 1). Hey, like I said earlier, this thing really is a cellular dustbin!

Figure 1. Parts of the 26S proteasome- a cellular dustin

They found that ASK1 interacts with the 19S lids of the 26S proteasome, the parts responsible for tagging unwanted proteins and transferring them to the core to be mashed up. Specifically ASK1 seems to inhibit an enzyme in the 19S lid called ATPase Rpt5, which is  critical for normal 26 S proteasome activity.

The authors go on to hypothesise that ASK1’s ability to inhibit 26S proteasome activity through blocking ATPase Rpt5 may account for the reduction of 26S proteasome activity in stressful conditions in the cell, which can eventually lead to disease. If scientists can develop inhibitors of ASK1 to stabilize proteasome activity, and if any beneficial effects are translated from the bench into the clinic, they may provide much needed treatments for cancer, AIDs, and neurodegenerative diseases.

Lots of ‘ifs’, but only time will tell whether ASK1 is a new target for the future

Ref: http://www.jbc.org/content/285/47/36434.abstract

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‘Silent’ Cytomegalovirus Can Cause Intestinal Cancers in Mice: Significance in Humans Still Unclear

Figure 1. The CMV virus, which occurs in up to 90% of the worlds' population

Human Cytomelagovirus (CMV), which infects millions of people worldwide usually without any symptoms, appears to cause gastrointestinal cancers in mice, the significance in humans is not clear.

Up to 90% of the worldwide population are silently infected with CMV (Fig. 1), which generally is not associated with any symptoms, but is a persistent little blighter nonetheless. CMV infection can cause severe disease particularly in people with a weakened immune system such as transplant patients, and AIDS patients, and  developing fetuses. People with a healthy immune system can mount a vigorous immune response to keep the virus at bay; however, in people with a weakened immune system, the virus can rage out of control and cause severe disease which can be life threatening.

 Unlike other organisms, viruses do not replicate through cell division; instead they invade and exploit host cells to do their replication for them. To do this, they must first bind to a host cell, enter it, and then hijack the hosts’ cells machinery to replicate and produce more viruses in the so called ‘primary infection’ stage. CMV viral replication is typical amongst viruses in that during the hijack of a host cell, viral DNA integrates into host cell DNA resulting in the production of various genes needed for viral replication. There are several phases of gene expression: immediate-early, delayed early and late, based on the time from initial viral infection. Following primary infection, CMV can also enter into a latent phase when the virus enters a dormant state during which viral replication does not occur. However, CMV can be later be reactivated back to a replicative state which can occur in people with a weakened immune system.

During the immediate-early gene and latent phases  of a CMV infection a gene called US28 is produced. As CMV infection had previously been detected in the cells that line the gastrointestinal tract and since the role of US28 has only been investigated in in vitro studies, Bongers et al., chose to examine the role of US28 in tumor formation in cells lining the gastrointestinal tract of mice, as reported in this months’ issue of the Journal of Clinical Investigation. To do this, they created transgenic mice─ mice where extra genes are added to the genome (Fig. 2)─ in this case the US28 gene was specifically targeted to cells in the lining layer of the mouse gut [Fig. 3]) and the lining layer of the gut was examined to see if there were any cancerous changes.

Figure 2. Creation of US28 transgenic mice

Figure 3. US28 expression in the gastrointestinal lining layer of US28 transgenic mice

In US28 transgenic mice, they found that US28 had the ability to induce cancer by increasing cell proliferation in the cells lining the gut through activating of specific intracellular signaling molecules (wnt and MAPK). US28 transgenic mice also went on to develop intestinal cancers.

As patients with inflammatory bowel disease have an increased risk of developing colon cancer, they examined whether CCL2, which is expressed in many inflammatory conditions and inflammatory bowel disease, increased the ability of US28 to induce cancer which it did.

The authors conclude that US28 produced by CMV promotes the development of cancer in transgenic mice and suggest that CMV infection may facilitate the development of gastrointestinal cancers in humans. In addition, inflammatory factors such as CCL2 can increase the oncogenic activity of US28. Although this is the first in vivo study of it’s type and builds on previous in vitro studies which have implicated US28 and CMV in the development of cancer, it falls way short of drawing any firm conclusions that CMV could cause cancer in humans. In fact, drawing any such conclusions would be unwise as this is more of a hypothesis-generating study which could form the basis of further research to analyse the association between CMV and intestinal cancer in humans.

Reference: http://www.jci.org/articles/view/42563/pdf

Bone Drugs May Thwart Development of Cancer ‘Seeds’

What do cancer cells and seeds have in common? The way that they spread to a new site and germinate it seems.

When a plant goes to seed, its seeds are carried in lots of different directions, but they can only grow and develop if they land on soil which is conducive to growth. Similarly, it is now well known that when cancer spreads secondary tumors (or metastases) do not develop by chance, as some organs provide a more fertile soil for tumor growth than others. These ideas form a long-running hypothesis in cancer research called the ‘seed and soil’ hypothesis.

A recent editorial in the Journal of Clinical Oncology this week by Dr Michael Gnat, further reinforces this hypothesis for cancer development, and that a certain group of bone cancer drugs, bisphosphonates, might create an “unfavorable soil” in which the development of cancer cells is thwarted.

Bisphosphonates are the treatment of choice for preventing bone loss and fractures in postmenopausal women with osteoporosis. They are also being investigated as treatment for preventing cancer-induced bone loss in women with early-stage breast cancer. Importantly, they have demonstrated anti-cancer activity in the lab and in clinical studies, which have shown that they:  block the release of factors that promote tumor growth and angiogenesis (growth of the tumors blood supply), induce cancer cell death (or apoptosis), prevent cancer cells sticking to each other, reduce the ability of cancer cells to spread via blood vessels, and activate the immune system to attack cancer cells. 

Based on this background information, several studies have been set up to determine whether bisphosphonates given to women with postmenopausal osteoporosis may reduce the risk of breast cancer, including two studies reported in the same issue of the Journal of Clinical Oncology.

In the first study by Chlebowski et al., approximately 150,000 women who received bisphosphonates for osteoporosis had a 32% reduction in the risk of breast cancer versus those who did not receive bisphosphonates. In a separate study by Rennert et al., a 28% reduction in the risk of breast cancer was reported in women receiving bisphosphonates for more than 1 year.

‘At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy’

However, these results should be considered with caution as the authors note that several factors may have influenced the results, including age, ethnicity, and tobacco use to name but a few, says Dr Gnat. As a result, he states, ‘these analyses should be viewed as hypothesis generating and not practice changing at this time’…. ‘At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone protecting effects’.

‘Bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing cancer’

Dr Gnat also states ‘The statistically significant reductions in breast cancer risk associated with bisphosphonate use “are profound and intriguing, because they suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing breast cancer,”. He goes on to say that these significant results are ‘profound and intriguing’ as they ‘suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing cancer’. He also suggests that these results support the idea that the seed and soil hypothesis is relevant to both healthy postmenopausal women as well as in preventing recurrence in women with early-stage breast cancer.

In conclusion, Dr Gnat suggests that future anticancer treatments may target the tumor microenvironment in addition to the cancer cells themselves.

References:

1. http://jco.ascopubs.org/cgi/content/full/28/22/3548

2. http://jco.ascopubs.org/cgi/content/abstract/28/22/3577

3. http://jco.ascopubs.org/cgi/content/abstract/28/22/3582

All Roads Lead to Blocking Androgen Signaling in Castrate-Resistant Prostate Cancer, But Which Road is Best?

Things are hotting up in the prostate cancer field, with scientists discovering several new targets that may provide hope for patients with late-stage prostate cancer.

Androgens (testosterone and dihydrotestosterone) are known to fuel the growth of prostate cancers as they bind the androgen receptor (AR) driving signaling pathways that driving tumor cell proliferation and tumor development. To halt the effects of androgens binding the AR, androgen deprivation therapy (ADT) is used to try and block the levels of circulating androgens and prevent them from fuelling tumor growth.

Despite ADT reducing androgen levels to very low or ‘castrate’ levels, castrate-resistant prostate cancer (CRPC) typically develops in most patients who initially respond to treatment. The precise mechanisms underlying this resistance are just starting to be worked out, but it seems that that ADT does not fully ablate androgen synthesis in the adrenal glands (where androgen synthesis normally occurs)  nor in the tumor itself where recently it has been discovered that androgen synthesis also occurs.

Once CRPC develops, the time to death is about 2 years and treatment options in this patient population are limited, demonstrating a high unmet need for treatments that prolong survival in these patients.

Androgens are synthesized from cholesterol involving complex enzymatic pathways, which includes the enzyme 3 beta-hydroxysteroid dehydrogenase which takes inactive precursors (DHEA and A5diol) and converts them to the more active androgens, androstenedione and testosterone, which are later converted to dihydrotestosterone. If this enzyme is active in prostate tumors, testosterone and dihydrotestosterone could in theory bind the AR and continue to fuel tumor growth. In a recent study in the journal Endocrinology, Evaul et al., discovered that was the case with 3 beta-hydroxysteroid dehydrogenase being necessary for producing testosterone and dihydrotestosterone in models of CRPC, which then activates the AR, driving tumor cell proliferation. As a result, this enzyme is thought to provide an attractive new target for the treatment of CRPC.

At the moment this is just a hypothesis that needs to be tested in the clinic. However, there are similar agents currently in later stages of development, including abiraterone and TAK700 which inhibit another enzyme in the androgen synthesis pathway (CYP17,20), MDV3100 which blocks androgens binding the AR, and VN/124-1 which both inhibits CYP17,20 and blocks androgens binding the AR. These are indeed exciting times for prostate cancer patients.

Reference: http://endo.endojournals.org/cgi/content/abstract/151/8/3514

Going Bananas Over a Bug Provides New Insights into How Prostate Cancer Develops

I’ve never been to the French West Indies, and I’ve never heard of the banana root borer (a larvae which tunnels through banana corms- admit it, you were wondering!), but this little critter has sparked some insightful research into what causes prostate cancer.

Unlike other cancers, little is known about the risk factors for prostate cancer with increasing age, ethnicity (Afro-Carribean men have an increased risk of prostate cancer for example) and family history of the disease being the only known risk factors.

The key drivers of prostate cancer development are androgens which bind the androgen receptor (AR) in prostate cancer cells and promote tumor development; however, estrogens are also thought to be involved as estrogen receptors (ERs) have been found in the prostate and in vitro studies have shown that binding of estrogens or estrogen-like molecules (also known as endocrine disruptors) to these receptors (ER alpha and beta) can result in prostate cancer development in tumor models.

Chlordecone (also known as Kepone) is an insecticide which has estrogenic-like properties in that it can bind ER alpha and beta and therefore has similar physiological properties to estrogen. Notably, the incidence of prostate cancer is particularly high in the French West Indies, where chlordecone was used for over 30 years to kill the banana root borer larvae.

Based on these findings, Luc Multigner and colleagues from Universitaire de la Guadeloupe in the French West Indies, measured exposure to chlordecone by measuring it’s concentration in the serum of 623 prostate cancer patients and 721 control patients exposured to this agent for over 30 years and found that it was consistently associated with an increased risk of prostate cancer. Prostate cancer risk was higher in subjects with a family history of prostate cancer, suggestive of similar patterns of exposure to chlordecone possibly through genetic susceptibility to the toxic effects of this agent. In addition, prostate cancer risk was increased for those men who had lived in Western countries, possibly attributed to lifestyle and nutritional changes which could increase the risk of developing prostate cancer.

The authors hypothesise that chlordecone acts as an ERalpha agonist and an ERbeta antagonist in the prostate. It is unclear how chlordecone exactly causes prostate cancer, but it is thought that the balance between the bad cancer causing effects mediated through ERa (increasing cell proliferation and inflammation) and the good anti-cancer effects (antiproliferative and ant inflammatory) mediated by ERbeta may be tipped in favor of the bad estrogen- ERalpha.

This is the first epidemiologic study to demonstrate a link between between environmental exposure to endocrine disruptors and prostate cancer development, and will heighten the debate surrounding the use of these agents and their potential risks for humans.

Reference: Journal of Clinical Oncology: http://jco.ascopubs.org/cgi/reprint/28/21/3457