Abstract
BAG3, member the HSP70 co-chaperones family, has been shown to play a relevant role in the survival, growth and invasiveness of different tumor types. In this study, we investigate the expression of BAG3 in 66 specimens from different lung tumors and the role of this protein in small cell lung cancer (SCLC) tumor growth. Normal lung tissue did not express BAG3 while we detected the expression of BAG3 by immunohistochemistry in all the 13 squamous cell carcinomas, 13 adenocarcinomas and 4 large cell carcinomas. Furthermore, we detected BAG3 expression in 22 of the 36 SCLCs analyzed. The role on SCLC cell survival was determined by down-regulating BAG3 levels in two human SCLC cell lines, i.e. H69 and H446, in vitro and measuring cisplatin induced apoptosis. Indeed down-regulation of BAG3 determines increased cell death and sensitizes cells to cisplatin treatment. The effect of BAG3 down-regulation on tumor growth was also investigated in an in vivo xenograft model by treating mice with an adenovirus expressing a specific bag3 siRNA. Treatment with bag3 siRNA-Ad significantly reduced tumor growth and improved animal survival. In conclusion we show that a subset of SCLCs over express BAG3 that exerts an anti-apoptotic effect resulting in resistance to chemotherapy.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for over 200,000 new cases and over 160,000 deaths per year in the United States, the most aggressive form being small cell lung cancer (SCLC) that accounts for >12% of all lung cancer diagnoses
We suggest that evaluation of Bcl2-associated athanogene 3 (BAG3) expression might be a potentially useful classification tool for SCLCs
BAG3 is an anti-apoptotic protein that has been shown to sustain cell survival in a variety of tumor types [5, 6, 9, 10], and its down-regulation appears to induce cell apoptosis and impair tumor growth in SCLC cells suggesting that it may represent a novel target for therapy in positive tumours
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for over 200,000 new cases and over 160,000 deaths per year in the United States, the most aggressive form being small cell lung cancer (SCLC) that accounts for >12% of all lung cancer diagnoses. It is has been shown to be constitutive in several primary tumors and tumor cell lines (pancreatic cancer, melanoma, leukemias, and others) [3, 4] and has been shown to play an important role in tumor biology [3, 4, 5, 6, 7, 8]. It has been suggested that its role in tumors is due to its anti-apoptotic properties BAG3 has been shown to protect cells from death through a number of mechanisms that in general involve interaction with apoptosis- regulating proteins, including the IKK gamma subunit of the NF-κB- activating complex IKK [5], Bax [9], BRAF [10] and others [3]
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