Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion.
Malignant pleural mesothelioma (MPM) is a deadly disease with few systemic treatment options. One potential therapeutic target, the non-receptor tyrosine kinase c-Src, causes changes in proliferation, motility, invasion, survival, and angiogenesis in cancer cells and may be a valid therapeutic target in MPM. To test this hypothesis, we determined the effects of c-Src inhibition in MPM cell lines and examined c-Src expression and activation in tissue samples. We analyzed four MPM cell lines and found that all expressed total and activated c-Src. Three of the four cell lines were sensitive by in vitro cytotoxicity assays to the c-Src inhibitor dasatinib, which led to cell cycle arrest and increased apoptosis. Dasatinib also inhibited migration and invasion independent of the cytotoxic effects, and led to the rapid and durable inhibition of c-Src and its downstream pathways. We used immunohistochemical analysis to determine the levels of c-Src expression and activation in 46 archived MPM tumor specimens. The Src protein was highly expressed in tumor cells, but expression did not correlate with survival. However, expression of activated Src (p-Src Y419) on the tumor cell membrane was higher in patients with advanced-stage disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Y419. Lower levels of membrane expression of inactive c-Src (p-Src Y530) correlated with advanced N stage (P = 0.02). Activated c-Src may play a role in survival, metastasis, and invasion of MPM, and targeting c-Src may be an important therapeutic strategy.
Tsao
Anne S
AS
Department of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030, USA. astsao@mdanderson.org
He
Dandan
D
Saigal
Babita
B
Liu
Suyu
S
Lee
J Jack
JJ
Bakkannagari
Srinivasa
S
Ordonez
Nelson G
NG
Hong
Waun Ki
WK
Wistuba
Ignacio
I
Johnson
Faye M
FM
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000069439:Dasatinib; D004789:Enzyme Activation / Q000187:drug effects; D005091:Exons / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008654:Mesothelioma / Q000201:enzymology / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010997:Pleural Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib