How Prostate Cancer Cells Survive Glucose Deprivation

Illustration of energy metablism in cell.Glucose is an energy metabolite necessary for cellular survival and growth whether or not the cell is part of a tumor. Not only do cancer cells switch from oxidative phosphorylation to aerobic glycolysis (the Warburg effect) to gain more glucose, a hallmark of cancer, but they also increase the amount of glucose taken up from the surrounding extracellular space. However, the lack of glucose can have a negative effect on cells, causing them to become apoptotic in the absence of this metabolite. Cancer cells have methods to get around the requirement for glucose, including upregulating glucose transporters to improve access to the energy metabolite. In this Redox Biology article, researchers describe how activating androgen receptor in response to a lack of glucose affects the amount of GLUT1 expressed on prostate cancer cells, making the cells resistant to glucose deprivation.

To set the stage, two prostate cancer cell lines, LNCaP, an androgen-sensitive cell line, and LNCaP-R, an androgen-insensitive cell line, were deprived of glucose. Both cell lines showed signs of cell death, but LNCaP-R cells died in greater numbers. To probe how LNCaP cells died, several inhibitors (a pan-caspase inhibitor, two necroptosis inhibitors and a ferroptosis inhibitor) were added but did not change the way the cells died. However, an autophagy inhibitor enhanced cell death, suggesting the cells were necrotic not apoptotic. Teasing apart if the necrosis of LNCaP cells was due to glucose availability or merely disrupted glycolysis, the glucose analog 2DG was added to the medium with glucose. The cells survived when treated with 2DG, suggesting it was the absence of glucose that induced necrosis. When LNCaP cells were cultivated in medium that replaced glucose with mannose or fructose, the cells survived, another point in favor of sugar depletion causing cell death. Continue reading

Long-Lasting Beauty from the Humble Egg

“The Coronation of the Virgin” tempera on panel by Fra Angelico [Public domain], via Wikimedia Commons

Chicken eggs are widely found in most grocery stores. They are a cheap and unassuming source of protein, easy to cook as you desire (e.g., fried, scrambled, hard boiled) or use as a binder for other food items (e.g., meatloaf, cakes, cookies). One reason I keep laying hens myself is not only for fresh eggs but also to have egg shells other colors than white, the predominant color sold in US grocery stores. However, did you know that eggs have uses that don’t end up in the stomach and instead, are a feast for the eyes? I was introduced to the concept of egg tempera, a medium used for painting, by my colleague, Karen Stakun, artist and manager of our graphics department during a discussion about chickens. I was intrigued by the concept. Continue reading

Finding Its Place: The Biohealth Industry in Wisconsin

On October 9, the 2018 Wisconsin Biohealth Summit was held in Madison, WI, hosted by BioForward, an organization that supports the growth of the biohealth industry in the state. This day-long event covered topics such as how diversifying your team can build better leadership, discovering new markets for existing products, and biomanufacturing. One of the panels on the schedule was “Examining the Economic Impact of Wisconsin’s Biohealth Industry,” and Penny Patterson, our Vice President of Communications, was one of the panel participants. We spoke after the summit to learn what came out of the panel discussion and the topics of interest raised by the biohealth industry attendees.

As we talked, Penny explained many topics were discussed, but ultimately focused around how to attract talented individuals to the biohealth industry in Wisconsin. This concern stemmed in part from the lower profile of the biohealth industry in Wisconsin compared to the more prominent and well-known East and West coasts. Of note, education and quality of life are important tools for recruiting candidates to join the biohealth industry. Continue reading

In Defense of Wild Spaces in the Yard

Pale purple asters and milkweed. Copyright S. Klink.

Surrounding my mowed lawn is a wild, mostly uncultivated space that currently has goldenrod blooming with tall asters starting to blossom. Every day when I pass these flowers, I see bumblebees, butterflies and other insects collecting the nectar to eat or store for the winter. Last year, when a section of soil was disturbed during construction of a building, I decided to seed the area with native wildflowers rather than grass. (I am not a fan of mowing the lawn.) Watching the series of flowers bloom over the late spring to autumn has been beautiful, colorful and full of tiny moments of joy. Not only do I see insects enjoying the flowering plants, but birds will land on the taller greenery, sometimes just resting, sometimes collecting seeds. I am not sure who has been startled more often, me or the birds when I walk by, flushing a bird from the thicket of tall plants.

Monarch butterfly on thistle photographed in the prairie at Promega headquarters in Madison, WI. Copyright Promega Corporation.

Where some people might see wild, unruly areas, I see Monarch butterflies on their daily flight, fluttering above me and the “weeds”. I have even been lucky enough to find Monarch caterpillars munching on milkweed, a common plant in my wild space. Despite my efforts, I have a lot of tall ragweed appearing in my yard, but have discovered that birds love the seeds, including my chickens, and squirrels will remove and eat the leaves. In addition, I see fireflies in early June through late August, many I find hanging out on the shady greenery during the day before their light display at night. Continue reading

How Autophagy Feeds Cancer’s Need for Metabolites

Illustration of energy metablism in cell.Metabolism underpins numerous cellular processes. Without it, cells would not grow, divide, synthesize or secrete. Another pathway, autophagy, degrades unwanted cellular materials, helping to maintain cell health. With these opposing roles, is there a connection between autophagy and metabolism? As it turns out, the answer is yes. Because molecules degraded by autophagy are recycled and fed into metabolism pathways as precursor compounds. There are interesting implications as a result of this connection, ones that affect cancer cells as described in a recent Cell Metabolism review article.

Autophagic flux, the process by which molecules and organelles are directed to the autophagosome, fuse with the lysosome and are degraded, involves a selective process that determines the cargo carried within the autophagosome. Autophagy-related genes (ATGs) direct the process and particular receptor proteins bind the cargo. What is interesting about the connection among cancer, autophagy and metabolism is the complexity of the role that autophagy plays in cancer. While autophagy was thought to act in a more tumor suppressive manner as shown when one copy of an ATG6 analogous gene in mice was deleted and the other left unaltered, and malignant tumors developed, but in mice mosaic for ATG5 deletions, the inhibition of autophagy resulted in benign tumors in the liver. This latter experiment suggested autophagy was needed for cancer progression, a hypothesis reinforced by the lack of ATG mutations in human cancers. Continue reading

All You Need is a Tether: Improving Repair Efficiency for CRISPR-Cas9 Gene Editing

Ribonucleoprotein complex with Cas9, guide RNA and donor ssDNA. Copyright Promega Corporation.

With the advent of genome editing using CRISPR-Cas9, researchers have been excited by the possibilities of precisely placed edits in cellular DNA. Any double-stranded break in DNA like that induced by CRISPR-Cas9 is repaired by one of two pathways: Non-homologous end joining (NHEJ) or homology-directed repair (HDR). Using the NHEJ pathway results in short insertions or deletions (indels) at the break site, so the HDR pathway is preferred. However, the low efficiency of HDR recombination to insert exogenous sequences into the genome hampers its use. There have been many attempts at boosting HDR frequency, but the methods compromise cell growth and behave differently when used with various cell types and gene targets. The strategy employed by the authors of an article in Communications Biology tethered the DNA donor template to Cas9 complexed with the ribonucleoprotein and guide RNA, increasing the local concentration of the donor template at the break site and enhancing homology-directed repair. Continue reading

Finding Chinks in the Armor: Cancer’s Need for Metabolites

Illustration of energy metablism in cell.Cancer has been studied for decades by scientists trying to find a vulnerability to exploit and testing compounds to develop as potential drugs. As the “Emperor of All Maladies”, cancer has proven itself to be a wily beast with many varieties of genetic mutations for eluding cellular control, tireless in its ability to divide and spread. In the end, a cancer cell is still a cell and subject to its environment even though cancer does not play by the same rules as the normal cells that exist around it. To be able to grow, a cell needs access to metabolites, molecules needed for building the materials and machinery needed by the cell to function and divide. These requirements also offer potential pathways to target for halting cancer growth and spread.

All cells use glucose to generate ATP, but normal and cancer cells differ in how glucose is converted to ATP. Most cells use glucose in oxidative phosphorylation, but cancer cells use aerobic glycolysis, converting glucose to lactate without oxygen. This Warburg effect (glucose converted to lactate) is a hallmark of cancer cells as they take up glucose at a much higher rate than normal cells. Blocking glucose uptake is one way to target cancer cells. While 2-deoxyglucose (2DG) has been shown to slow glucose uptake in vitro, the compound proved toxic in clinical trials and lower dosages do not seem to be an effective treatment against cancer. While not an ideal drug target, glucose uptake has been helpful in monitoring cancer response to therapies via fluorodeoxyglucose positron emission tomography (FDG-PET). Continue reading

Genomic Breakthroughs One Letter at a Time

In honor of Human Genome Month, I delved into our Cartoon Lab archives to retrieve this example of the excitement that occurred while sequencing the Human Genome Project.

For more entertaining science cartoons, visit our Cartoon Lab.

Science News: Demoting Termites, Monitoring Blood Pressure with Your Smartphone and Finding Amelia Earhart’s Bones

A few science news items caught my eye this week.

Macro image of a termite (Isoptera) found under a rock. Image by Sanjay Acharay via Wikimedia Commons.

Wood-Shattering Revelation: Termites have been recategorized based on genetic and other evidence. Turns out, they are just social cockroaches and thus, have become part of the cockroach order Blattodea rather than remaining in a separate order. This decision was not made lightly, but based on years of debate amongst American entomologists. The insects will still retain termite in their name, but they gain a reputation for surviving apocalyptic events. Read about the update to the insect name master list by the Entomological Society of America.

Sphygmomanometer with cuff, used to measure blood pressure via Wikimedia Commons.

Blood Pressure Measurements at the Tip of Your Finger: A blood pressure cuff is bulky, annoying but accurate for monitoring the effort needed for pushing blood around your body. While this device is a fairly simple one, in the developing world it is not that common. However, mobile phones are available to many more globally so why not find a way to put the two together? Turns out that smartphones are equipped with hardware that can be used to measure blood pressure. By adding a device that attaches to the back of a smartphone and with the press of a finger, you can monitor your blood pressure. While not currently as accurate as a blood pressure cuff, the people that tried the mobile blood pressure device were able to quickly adapt to using it, making it easy to take several readings for continuous monitoring. A pocket-sized blood pressure monitor without the nasty squeeze of your arm sounds like a great medical advancement for treating high blood pressure. See a video of the device.

Photo of Amelia Earhart and Dr. Edward C. Elliott, president of Purdue University with the Lockheed Electra she later disappeared in. Purdue University paid for the plane as Earhart was then a consultant on aeronautics there. Photo taken 20 August 1936.

For a Forensic ID, All You Needed Was a Picture, Old Clothing and Some Numbers: The quest to find where Amelia Earhart may have landed in the Pacific Ocean has been investigated and speculated about since she and her navigator disappeared July 2, 1937. In fact, skeletal remains had been found on a remote island in the South Pacific in 1940 along with other artifacts–a woman’s shoe, an American sextant box, but the bones were identified as a man by a physician at the time. Unfortunately, these remains have subsequently been lost. Recently, an anthropologist decided to take the measurements made in 1940, and using a modern-day techniques including a program that estimates stature, sex and ancestry, and he found that the bone measurements were more consistent with Earhart than with 99% of the reference sample used. In addition, using a photograph of the American pilot that had scale generated bone lengths of her humerus and radius and measuring her clothing from a collection gave a number for her tibia. All these numbers strongly suggest the skeletal remains were Earhart’s. Read the press release.

Celebrating Women in Science

By US Environmental Protection Agency [Public domain], via Wikimedia Commons

February 11 is the International Day of Women and Girls in Science, a reminder that there is still a gender gap in science. Despite the obstacles that women need to overcome, their contributions to field of science have benefited not only their fellow researchers but also their fellow humans. From treatments for diseases to new discoveries that opened up entire fields, women have advanced knowledge across the spectrum of science. Below is a sampling of the achievements of just a few women. What other living female scientist or inventor might you add?

Hate malaria? You can thank Tu Youyou for discovering artemisinin and dihydroartemisinin, compounds that are used to treat the tropical disease and save numerous lives. Her discovery was so significant, she received the 2015 Nobel Prize in Physiology or Medicine. Continue reading