Over-expression of adenine nucleotide translocase 1 (ANT1) induces apoptosis and tumor regression in vivo.
BACKGROUND
Adenine nucleotide translocase (ANT) is located in the inner mitochondrial membrane and catalyzes the exchange of mitochondrial ATP for cytosolic ADP. ANT has been known to be a major component of the permeability transition pore complex of mitochondria and contributes to mitochondria-mediated apoptosis. Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4), and the expression of the ANT isoforms is variable depending on the tissue and cell type, developmental stage, and proliferation status. Among the isoforms, ANT1 is highly expressed in terminally-differentiated tissues, but expressed in low levels in proliferating cells, such as cancer cells. In particular, over-expression of ANT1 induces apoptosis in cultured tumor cells.


METHODS
We applied an ANT1 gene transfer approach to induce apoptosis and to evaluate the anti-tumor effect of ANT1 in a nude mouse model.


RESULTS
We demonstrated that ANT1 transfection induced apoptosis of MDA-MB-231 cells, inactivated NF-kappaB activity, and increased Bax expression. ANT1-inducing apoptosis was accompanied by the disruption of mitochondrial membrane potential, cytochrome c release and the activation of caspases-9 and -3. Moreover, ANT1 transfection significantly suppressed tumor growth in vivo.


CONCLUSIONS
Our results suggest that ANT1 transfection may be a useful therapeutic modality for the treatment of cancer.
Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-799, South Korea. jjy93@hanmail.net
Ji-Young
JY
Jang
Yun
Y
Choi
Yoon-Kyung
YK
Jeon
Khin Chaw Yu
KC
Aung
Chul-Woo
CW
Kim
D033741:Adenine Nucleotide Translocator 1 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D033741:Adenine Nucleotide Translocator 1; D016328:NF-kappa B