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TCDD
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"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.
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