Src and epidermal growth factor receptor mediate the pro-invasive activity of Bcl-w.
Members of the Bcl-2 family are established regulators of cell death. However, recent studies have shown that they can also regulate cell migration, invasion, and cancer metastasis. These functions of cancer cells are promoted by pro-survival Bcl-2 proteins (Bcl-2, Bcl-XL, and Bcl-w) but are suppressed by pro-apoptotic members (Bax and Bak). We have previously shown that Bcl-w and Bcl-XL enhance the ability of respiratory complex-I to produce reactive oxygen species (ROS), stimulating the phosphoinositide 3-kinase (PI3K)-dependent invasion pathway. Here, we show that Bcl-w overexpression increases the phosphorylation of epidermal growth factor receptor (EGFR) and Src, and their interaction. Our results show that ROS production induced by Bcl-w activates Src, which then binds to and phosphorylates EGFR, leading to stimulation of the PI3K-dependent invasion pathway. Importantly, Bcl-w-induced cell invasion was prevented by treating cells with gefitinib (Iressa, ZD1839), an anticancer drug that directly inhibits EGFR. We also show that Bcl-XL can stimulate Src and EGFR phosphorylation, and that this function of Bcl-XL and Bcl-w is antagonized by Bax and Bak. Overall, this study demonstrates the involvement of Src and EGFR in the regulation of cellular invasiveness by Bcl-2 proteins, suggesting that chemotherapeutics targeting EGFR may be useful in preventing the progression of cancers that have altered Bcl-2 protein functions.
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Nowon-ro 75, Nowon-gu, Seoul, 139-706, Korea.
Eun Mi
EM
Kim
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Nowon-ro 75, Nowon-gu, Seoul, 139-706, Korea.
Jong Kuk
JK
Park
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Nowon-ro 75, Nowon-gu, Seoul, 139-706, Korea.
Sang-Gu
SG
Hwang
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Nowon-ro 75, Nowon-gu, Seoul, 139-706, Korea. hdum@kirams.re.kr.
Hong-Duck
HD
Um
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D000077156:Gefitinib
Bcl-2 family; Cancer; Cell invasion; EGFR; Src