The β6-integrin-ERK/MAP kinase pathway contributes to chemo resistance in colon cancer.
5-Fluorouracil (5-FU) is the most widely used chemo drug for the treatment of colon cancer. However, a sub-population of colon cancer patients do not respond to 5-FU and this treatment does not provide survival benefit due to chemo resistance. The mechanisms involved in 5-FU resistance are not fully understood and multiple factors have been involved in the sensitivity of cancer cells to 5-FU. We previously reported that β6-integrin plays an important role in invasion, metastasis and degradation of extracellular matrix of colon cancer. In this study, we investigated whether β6-integrin is associated with chemo resistance in colon cancer. We found that over-expression of β6-integrin protected SW480 and HT-29 colon cancer cells from 5-FU-induced growth inhibition and apoptosis, which were accompanied by changes in cytochrome C released from the mitochondria and activity of caspase-3 and caspase-9. Moreover, β6-integrin resulted in up-regulation of Bcl-2 and down-regulation of Bax. We also found that β6-integrin induced 5-FU resistance through the ERK/MAP kinase pathway and the β6-ERK2 direct binding. The results indicate β6-integrin might be a novel therapeutic target in colon cancer therapy.
Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong, PR China.
Song
S
Liu
Jian
J
Wang
Weibo
W
Niu
Enyu
E
Liu
Jiayong
J
Wang
Cheng
C
Peng
Pengfei
P
Lin
Ben
B
Wang
Abdul Qadir
AQ
Khan
Huijie
H
Gao
Benjia
B
Liang
Muhammad
M
Shahbaz
Jun
J
Niu
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D039641:Integrin beta Chains; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C072170:integrin beta6; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053453:Caspase 9; D005472:Fluorouracil