Depletion of PI3K p85alpha induces cell cycle arrest and apoptosis in colorectal cancer cells.
Colorectal cancer is one of the most common malignancies in the world. Overactivity of phosphatidylinositol 3-kinase (PI3K) is frequently detected in colorectal carcinoma. PI3K signaling plays a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation, and tumorigenesis. To specifically inhibit PI3K activity in colorectal cancer cells, we constructed a siRNA against the PI3K regulatory subunit p85alpha and transfected it into LoVo and SW480 cells. In the present study, treatment of colorectal cancer cells with PI3K p85alpha-specific siRNA inhibited cell proliferation, induced G1 phase cell cycle arrest and sensitized colorectal cancer cells to 5-FU-induced apoptosis. Furthermore, depletion of PI3K p85alpha resulted in significant activation of three Forkhead box class O (FoxO) transcription factors, which inhibited the expression of cyclin D1, cdk4 and induced expression of p27/Kip1. Activation of FoxO transcription factors also increased the expression of FasL. Thus, our results indicate that siRNA-mediated gene silencing of PI3K p85alpha may be a useful therapeutic strategy for colorectal carcinoma.
Sun
Yan
Y
Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
Zhao
Shiyi
S
Tian
Hua
H
Xie
Xiaoyun
X
Xiao
Faman
F
Li
Kang
K
Song
Yugang
Y
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation
C505661:FASLG protein, human; C085126:FOXO1 protein, human; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases