Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma.
OBJECTIVE
The phosphatidylinositol 3-kinase (PI3K) pathway promotes cancer cell proliferation and survival. The authors determined the pattern of distribution of PI3K pathway components (ie, the p85alpha regulatory subunit, p110alpha catalytic subunit, Akt1, Akt2, and the tumor suppressor PTEN) in human colorectal cancer. In addition, inhibition of in vitro proliferation and in vivo liver metastasis by p85alpha or p110alpha siRNA treatment was analyzed.


BACKGROUND
Small interfering RNA (siRNA) molecules suppress expression of target genes and may have therapeutic applications as target-specific therapies for cancer. Therefore, the purpose of this study was 2-fold: 1) to analyze the distribution pattern of PI3K pathway components in human normal colorectal cancers, and 2) to determine whether targeted inhibition of PI3K inhibits colon cancer growth in vitro and suppresses metastatic growth in vivo.


METHODS
Immunohistochemical analysis was performed on colorectal adenocarcinomas and adjacent normal mucosa for PI3K pathway components, including p85alpha, p110alpha, Akt1, Akt2, and the tumor suppressor PTEN, which inhibits PI3K. HT29 and KM20 human colon cancer cells were treated with siRNA directed to p85alpha or p110alpha, and cell viability and apoptosis assessed. HT29 cells, transfected with a plasmid containing green fluorescent protein (GFP), were injected into the spleen of athymic nude mice to establish liver metastases; mice were randomized to receive either nontargeting control (NTC), p85alpha or p110alpha siRNA.


RESULTS
PI3K pathway components p85alpha and Akt2 were highly expressed in glandular elements of colon cancers, with a correlation between staining intensity and clinical stage; PTEN expression was decreased in the colon cancers of all stages. PI3K-specific siRNA treatment decreased cell viability in vitro and suppressed metastatic tumor growth in vivo.


CONCLUSIONS
Selective targeting of PI3K pathway components may enhance the effects of standard chemotherapeutic agents and provide novel adjuvant treatment of selected colorectal cancers.
Rychahou
Piotr G
PG
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA.
Jackson
Lindsey N
LN
Silva
Scott R
SR
Rajaraman
Srinivasan
S
Evers
B Mark
BM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012334:RNA, Neoplasm / Q000235:genetics*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering