Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells.
BACKGROUND
The prognosis of advanced or recurrent colorectal cancer is still poor. Dye-effluxing side population (SP) colon cancer cells are reportedly resistant to chemotherapeutic agents. Most sporadic colorectal cancers involve constitutive activation of the Wnt signaling pathway. In this study, we examined the effect of the Wnt signaling on SP cells and the possibility that inhibition of Wnt signaling may decrease the resistance to chemotherapeutic drugs in the human colon cancer cells.


METHODS
Drug resistance of SP cells to 5-fluorouracil (5-FU) and irinotecan, decrease of SP cells by the Wnt signaling inhibition and activation of the Wnt signaling of the sorted SP cells were examined using the SW480 colon cancer cell line. mRNA expressions of ATP-binding cassette (ABC) transporters when Wnt signaling was inhibited were evaluated with real-time PCR using colon cancer cell lines (SW480, DLD-1, HCT116, HT29 and LOVO). The sensitivity to irinotecan and paclitaxel when the Wnt signaling was inhibited was investigated using SW480. Inhibition of Wnt signaling was performed by siRNA of beta-catenin.


RESULTS
SP cells showed more resistance to 5-FU and irinotecan, and higher activation of the Wnt signaling pathway, than non-SP cells. Silencing of beta-catenin decreased significantly more SP cells than non-SP cells. Expression of ABC transporter genes, such as ABCB1 and ABCG2, was significantly higher in SP cells than non-SP cells. Silencing of beta-catenin decreased transcription of these ABC transporter genes; beta-catenin-silenced cells became relatively sensitive to paclitaxel and irinotecan.


CONCLUSIONS
These results indicate that inhibiting the Wnt signaling pathway may be a fruitful strategy for targeting chemotherapy-resistant colon cancer cells, including SP cells.
Chikazawa
Nobuhito
N
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Tanaka
Haruo
H
Tasaka
Takehiko
T
Nakamura
Masafumi
M
Tanaka
Masao
M
Onishi
Hideya
H
Katano
Mitsuo
M
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin