Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer.
Molecular targeting for apoptosis induction is being developed for better treatment of cancer. Downregulation of 15-lipoxygenase-1 (15-LOX-1) is linked to colorectal tumorigenesis. Re-expression of 15-LOX-1 in cancer cells by pharmaceutical agents induces apoptosis. Antitumorigenic agents can also induce apoptosis via other molecular targets. Whether restoring 15-LOX-1 expression in cancer cells is therapeutically sufficient to inhibit colonic tumorigenesis remains unknown. We tested this question using an adenoviral delivery system to express 15-LOX-1 in in vitro and in vivo models of colon cancer. We found that (i) the adenoviral vector 5/3 fiber modification enhanced 15-LOX-1 gene transduction in various colorectal cancer cell lines, (ii) the adenoviral vector delivery restored 15-LOX-1 expression and enzymatic activity to therapeutic levels in colon cancer cell lines, and (iii) 15-LOX-1 expression downregulated the expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and BcL-XL, activated caspase-3, triggered apoptosis, and inhibited cancer cell survival in vitro and the growth of colon cancer xenografts in vivo. Thus, selective molecular targeting of 15-LOX-1 expression is sufficient to re-establish apoptosis in colon cancer cells and inhibit tumorigenesis. These data provide the rationale for further development of therapeutic strategies to target 15-LOX-1 molecularly for treating colonic tumorigenesis.
Wu
Yuanqing
Y
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Fang
Bingliang
B
Yang
Xiulan Q
XQ
Wang
Li
L
Chen
Dongning
D
Krasnykh
Victor
V
Carter
Bing Z
BZ
Morris
Jeffrey S
JS
Shureiqi
Imad
I
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D001093:Arachidonate 15-Lipoxygenase; D053148:Caspase 3