(Press-News.org) A new paper from an interdisciplinary team at MUSC Hollings Cancer Center describes how the bacteria Porphyromonas gingivalis interferes with chemotherapy-induced mitophagy, allowing oral cancer tumors to become resistant to the drug’s effects.
Besim Ogretmen, Ph.D., SmartState Endowed Chair in Lipidomics and Drug Discovery in the College of Medicine, and Ӧzlem Yilmaz, D.D.S., Ph.D., a professor, clinician-scientist and microbiologist in the College of Dental Medicine, worked with graduate student Megan Sheridan and other Hollings researchers to uncover how P. gingivalis promotes chemotherapy resistance.
Their paper was published in iScience.
P. gingivalis is a bacterium found in the mouth. In a healthy mouth, P. gingivalis and other disease-causing bacteria are kept in check by beneficial bacteria. But when that balance is disrupted, P. gingivalis is a major contributor to periodontitis – severe gum disease that can destroy gums and the bones holding the teeth in place. P. gingivalis can enter and survive inside the first lining cells of mucosa in the mouth, and then the microorganism can invade deeper tissue and spread systemically. Increasingly, it is being implicated in other diseases like Alzheimer’s, diabetes and gastrointestinal cancers.
It’s also been observed that oral cancer patients infected with P. gingivalis have worse outcomes. This paper maps out how that could be occurring, focusing on how intracellular P. gingivalis prevents ceramide-dependent mitophagy in oral squamous cell carcinomas.
Mitophagy, a specific form of autophagy, is the removal of damaged mitochondria. Ceramide is a sphingolipid that plays a key role in starting the process of lethal mitophagy.
“We understood that P. gingivalis is interfering with the lethal autophagy, making the cells not go to cell death – which is something you do not want,” Yilmaz said. “We needed to understand which part of the bacterium is interacting with those host molecules to create this resistance, or this protection against lethal mitophagy.”
After a few dead ends, the team homed in on the fimbriae – protruding pili-like protein structures on the outside of the bacteria. Whereas pili’s function is sensing or synchronized movement to move fluids or objects, the fimbriae’s major role is to attach.
“This molecule has been studied in this bacterium in a variety of contexts, like attaching to other bacteria, attaching to the collagen, attaching to fibrinogen. But it’s not like it’s just attaching to anything. It’s a very specific event,” Yilmaz said.
Ogretmen, whose lab focuses on the regulation and function of bioactive sphingolipids, figured out where the interaction was occurring, while Yuri Peterson, Ph.D., a Hollings researcher in the College of Pharmacy, used prediction analysis to identify the strong interactions between the bundles of peptides and the ceramide drug, Yilmaz said. But it was Yilmaz who first suggested they look at the fimbriae.
“It was your insight,” Ogretmen pointed out to Yilmaz. “Because we didn’t know how this microorganism inhibited this chemotherapy effect. We tried many different things. Then Ӧzlem said, ‘Maybe you should try this protein.’ We looked, and that was it.”
The team’s work suggests that the fimbriae attach themselves to specific proteins on the mitophagic membrane, blocking the ceramide drug from its attachment point and therefore stopping the lethal mitophagy in its tracks.
“So then the next goal is, ‘Can we use antibiotics to inhibit the protrusion protein so that it cannot interfere?’” Ogretmen said.
A visiting summer student will start work on this question, he said.
Yilmaz noted that another question is how the variations in fimbriae affect their interference with mitophagy. There are many strains of P. gingivalis, and different strains may have modifications in the fimbriae structure that can affect its interactions with host target molecules.
Yilmaz said this research was possible only because of the individual expertise of each of the investigators in vastly different fields.
“It was a true collaboration,” Ogretmen agreed. “And we complement each other’s expertise.”
About MUSC Hollings Cancer Center
MUSC Hollings Cancer Center is South Carolina’s only National Cancer Institute-designated cancer center with the largest academic-based cancer research program in the state. The cancer center comprises more than 140 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $50 million and sponsors more than 200 clinical trials across the state. Dedicated to preventing and reducing the cancer burden statewide, the Hollings Office of Community Outreach and Engagement works with community organizations to bring cancer education and prevention information to affected populations. Hollings offers state-of-the-art cancer screening, diagnostic capabilities, therapies and surgical techniques within its multidisciplinary clinics. Hollings specialists include surgeons, medical oncologists, radiation oncologists, radiologists, pathologists, psychologists and other clinical providers equipped to provide the full range of cancer care. For more information, visit hollingscancercenter.musc.edu.
***
This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
END
In late 2019 the previously unremarkable galaxy SDSS1335+0728 suddenly started shining brighter than ever before. To understand why, astronomers have used data from several space and ground-based observatories, including the European Southern Observatory’s Very Large Telescope (ESO’s VLT), to track how the galaxy’s brightness has varied. In a study out today, they conclude that they are witnessing changes never seen before in a galaxy — likely the result of the sudden awakening of the massive black hole at its core.
“Imagine you’ve been observing a distant galaxy for years, and it always seemed calm and inactive,” ...
Gastrointestinal (GI) cancers, encompassing esophageal, gastric, small bowel, and colorectal carcinomas, represent a significant global health burden due to their high incidence and mortality rates. This review by M. Jesús Fernández-Aceñero et al. provides an in-depth analysis of the molecular characteristics, prognosis, and current therapeutic strategies for these malignancies, highlighting the latest advancements and challenges in the field.
Esophageal carcinoma is among the ten most prevalent tumors globally, with squamous cell carcinoma (SCC) being the most common subtype. ...
COLUMBUS, Ohio – Discovering that hepatitis E virus is associated with sperm in pigs suggests the virus may be both sexually transmitted and linked to male infertility, according to a new study.
Hepatitis E (HEV) is the leading cause of the acute viral liver infection in humans worldwide, mostly in developing regions where sanitation is poor. The virus is also endemic in pigs in the United States – though it is present mostly in organs rather than muscle, and is killed when the meat is cooked.
Because HEV has been linked to fatal pregnancy complications and reports of male infertility ...
Common complications of pregnancy affecting fetal size may be caused by irregularities in the transport of amino acids across the placenta—a finding with therapeutic implications. Intrauterine growth restriction (IUGR) and fetal overgrowth affect 15-20% of pregnancies worldwide. Abnormal fetal growth is strongly linked to the development of obesity, diabetes, and cardiovascular disease in later life. Placental transport of essential amino acids is decreased in human IUGR and increased in fetal overgrowth, but whether this was a cause or consequence was unclear. Fredrick Rosario-Joseph and colleagues created a line of mice ...
If the household cleaner emits a lemon-like odour, this may be due to a nitrile called citronellyl nitrile. These versatile chemical nitrile groups are also used in the manufacture of active pharmaceutical ingredients, superglue and chemical-resistant gloves. The prevalent production process used so far has required a chemical reaction of certain molecules with highly toxic cyanide. Margit Winkler from the Institute of Molecular Biotechnology at TU Graz, together with Ludmila Martínková from the Institute of Microbiology at the Czech Academy of Sciences, ...
Osteoporosis is a skeletal condition that leads to the weakening of bones, making them porous, fragile, and prone to breakage. A whopping 8.9 million fractures are caused by osteoporosis annually, with one fracture occurring every three seconds! The aging population is the most vulnerable to primary osteoporosis, given, their frailty, and often, requires long-term therapy and support. Advances in healthcare and the corresponding rise in the aging population have put a strain on available resources, underscoring the need for effective therapies against osteoporosis.
Induction of parathyroid hormone (PTH) signaling using the PTH-derived ...
The potential of quantum computers is currently thwarted by a trade-off problem. Quantum systems that can carry out complex operations are less tolerant to errors and noise, while systems that are more protected against noise are harder and slower to compute with. Now a research team from Chalmers University of Technology, in Sweden, has created a unique system that combats the dilemma, thus paving the way for longer computation time and more robust quantum computers.
For the impact of quantum computers to be realised in society, quantum researchers first need to deal with some major obstacles. So far, errors and noise stemming from, for example, ...
Who should be spared pain, hurt or disappointment, and who should be harmed? This internal dilemma accompanied the participants of the Milgram experiment, say experts from SWPS University. They have revisited the causes of obedience in that famous study and showed that the experimenter's physical proximity promote subjects' obedience, while the learner's physical proximity decreases it.
American social psychologist Stanley Milgram's demonstration of the human tendency to show extreme obedience to authority was one of the most ...
A new UC Riverside study shows soot from large wildfires in California traps sunlight, making days warmer and drier than they ought to be.
Many studies look at the effect of climate change on wildfires. However, this study sought to understand the reverse — whether large fires are also changing the climate.
“I wanted to learn how the weather is affected by aerosols emitted by wildfires as they’re burning,” said lead study author and UCR doctoral candidate James Gomez.
To find his answers, Gomez analyzed peak fire days and ...
PULLMAN, Wash. – Voters who are neither wealthy nor white are more likely to live in counties with fewer resources available to make sure ballots are counted on time, a new election index revealed.
Researchers developed the County Election Administration index, detailed in the Election Law Journal, to evaluate election performance by county rather than just by state. Election administration encompasses the policies and processes that ensure election access, integrity and accuracy. Despite voter fraud claims in the last presidential election, researchers found that overall election performance ...
