Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

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Novel tumor markers in non-small cell lung cancer detected both in serology and tissue.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21105 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21105-e21105 ◽

Cited By ~ 2

Author(s):

Saba Radhi ◽

Raed Alalawi ◽

Leonardo Mirandola ◽

Yuefei Yu ◽

Apurva Pandey ◽

...

Keyword(s):

Lung Cancer ◽

Flow Cytometry ◽

Cancer Patients ◽

Cell Lines ◽

Cancer Cell ◽

Lung Cancer Cell ◽

Rt Pcr ◽

Specific Antibodies ◽

Lung Cancer Patients ◽

Normal Tissues

e21105 Background: Cancer testis antigens (CTA) are a class of tumor associated antigens, showing a restricted expression in cancer, a strong immunogenicity and weak expression or absence in normal tissues. CTA are a growing family of proteins involved in signal transduction control. Sp17/AKAP4/PTTG1 have been previously investigated, showing promising results as a target antigens. Our aim was to investigate the expression of Sp17/AKAP4/PTTG1 in lung cancer patients. Methods: We analyzed 2 lung cancer cell lines, one normal bronchus cell line, a panel of normal tissues and patient’s cells by RT-PCR, flow-cytometry, immunocytochemistry (ICC), and immunofluorescence (IF). CTA immunogenicity was investigated by measuring circulating specific antibodies in the sera of lung cancer patients. PCR was performed by 35 amplification cycles. RNA integrity in each sample was checked by amplification of ß-actin. We studied the pattern of expression in patients with NSCLC according to histology, gender, and age. Results: Specimens from 11 patients were examined.CTA, Sp17, AKAP-4 and PTTG-1 are aberrantly expressed in lung cancer cell lines and primary cells from patients by RT-PCR, immunocytochemistry, and flow cytometry. ELISA analyses show the presence of circulating CTA-specific antibodies in the sera of lung cancer patients, indicating the immunogenicity of Sp17, AKAP-4 and PTTG-1. The mean age of patients was 60 years(range 57-76). Fifty eight percent were males(N=7). Seventy two percent (n=8) had adenocarcinoma. Six patients were stage IV at diagnosis. There was no difference in the pattern of expression between gender, stage or histology. Conclusions: We showed that CTA, Sp17, AKAP-4 and PTTG-1 can be detected in both sera and tissue of patients with NSCLC. They are potential therapeutic targets for immunotherapies. These may me useful in determining response to treatment as well as asses possible recurrence.

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