Agent orange chemical, dioxin, attacks the mitochondria to cause cancer

December 17, 2007

Researchers with the University of Pennsylvania School of Veterinary Medicine have demonstrated the process by which the cancer-causing chemical dioxin attacks the cellular machinery, disrupts normal cellular function and ultimately promotes tumor progression.

The team identified for the first time that mitochondria, the cellular sub-units that convert oxygen and nutrients into cellular fuel, are the target of tetrachlorodibenzodioxin, or TCDD. The study showed that TCDD induces mitochondria-to-nucleus stress signaling, which in turn induces the expression of cell nucleus genes associated with tumor promotion and metastasis.

The mechanism the research team has described is directly relevant to understanding incidences of breast and other cancers in human populations exposed to these chemicals. With a better understanding of this underlying cellular mechanism, researchers hope to improve their understanding of tumor growth and promotion.

"Now that we have identified this signaling mechanism we can look at ways to disrupt this complex chain of events,” said Narayah Avadhani, chair of the Department of Animal Biology at Penn’s School of Veterinary Medicine and the study’s lead investigator. “Our ultimate goal is to block the propagation of this mitochondrial stress signaling and inhibit the expression of the proteins that combine to assist cancer growth.”

A well-characterized mechanism of TCDD action occurs through activation of arylhydrocarbon receptors, AhR, by directly binding to the protein subunits. Activated AhR mediates the transcriptional activation of many genes including those involved in fatty acid metabolism, cell cycle regulation and immune response.

The present study, however, shows that TCDD starts the chain of events that promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling. A unique feature of this TCDD-induced signaling is that it does not involve the action of AhR but occurs through increased calcium levels in cells and activation of calcium responsive factors. A net result of signaling cascade is slowing down of cellular apoptosis, increased cell proliferation and tumor cell metastasis. Taken together, this study describes a novel mechanism of TCDD-induced tumor progression and emergence of metastatic cancer cells.

TCDD is the most toxic compound in the dioxin family. Formed as a by-product during waste incineration, paper, chemical and pesticide manufacturing, it was the toxic ingredient in Agent Orange and closed the Love Canal in Niagara Falls. The public health impact of dioxin, according to the Environmental Protection Agency, compares to that of the pesticide DDT.

The study appears online and in the Dec. 17 issue of the Proceedings of the National Academy of Sciences and was performed by Avadhani, Gopa Biswas, Satish Srinivasan and Hindupur Anandatheerthavarada of the Penn School of Veterinary Medicine.

Source: University of Pennsylvania

Explore further: Researchers identify new treatment target for melanoma

Related Stories

Researchers identify new treatment target for melanoma

January 16, 2018
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a new therapeutic target for the treatment of melanoma. For decades, research has associated female sex and a history of previous ...

First-in-class ERK1/2 inhibitor safe, shows early efficacy in patients with advanced solid tumors

December 15, 2017
The novel ERK1/2 kinase inhibitor ulixertinib displayed an acceptable safety profile and had clinical activity in patients whose tumors had mutations in the MAPK cell-signaling pathway, according to data from a phase I clinical ...

New pathway identified as a target for precision medicine against a common brain tumor

November 2, 2017
St. Jude Children's Research Hospital scientists have discovered a promising target for precision medicines to block a mechanism that drives several cancers, including about 30 percent of cases of the brain tumor called medulloblastoma. ...

Cellular network identified that 'short circuits' the antitumor effect of immunotherapies

November 13, 2017
Researchers from The Wistar Institute discovered a novel form of crosstalk among tumor cells and other cell types in the tumor microenvironment, elucidating the mechanism of action of an immunotherapeutic strategy that inhibits ...

New study points the way to therapy for rare cancer that targets the young

November 21, 2017
After years of rigorous research, a team of scientists has identified the genetic engine that drives a rare form of liver cancer. The findings offer prime targets for drugs to treat the usually lethal disease, fibrolamellar ...

Th1/17 hybrid T cells offer potent and durable anti-tumor response in preclinical model

November 9, 2017
Adoptive cell therapy for cancer involves harvesting T cells from a patient and expanding and sometimes modifying them in the laboratory before reinfusion. It has been challenging to create T cells that are both potent and ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.