1 research outputs found
RNA Interference against ATP as a Gene Therapy Approach for Prostate Cancer
Chemotherapeutic agents targeting energy metabolism have
not achieved
satisfactory results in different types of tumors. Herein, we developed
an RNA interference (RNAi) method against adenosine triphosphate (ATP)
by constructing an interfering plasmid-expressing ATP-binding RNA
aptamer, which notably inhibited the growth of prostate cancer cells
through diminishing the availability of cytoplasmic ATP and impairing
the homeostasis of energy metabolism, and both glycolysis and oxidative
phosphorylation were suppressed after RNAi treatment. Further identifying
the mechanism underlying the effects of ATP aptamer, we surprisingly
found that it markedly reduced the activity of membrane ionic channels
and membrane potential which led to the dysfunction of mitochondria,
such as the decrease of mitochondrial number, reduction in the respiration
rate, and decline of mitochondrial membrane potential and ATP production.
Meanwhile, the shortage of ATP impeded the formation of lamellipodia
that are essential for the movement of cells, consequently resulting
in a significant reduction of cell migration. Both the downregulation
of the phosphorylation of AMP-activated protein kinase (AMPK) and
endoplasmic reticulum kinase (ERK) and diminishing of lamellipodium
formation led to cell apoptosis as well as the inhibition of angiogenesis
and invasion. In conclusion, as the first RNAi modality targeting
the blocking of ATP consumption, the present method can disturb the
respiratory chain and ATP pool, which provides a novel regime for
tumor therapies.