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|Ref Type||Journal Article|
|Authors||Aggarwal S, Kim SW, Ryu SH, Chung WC, Koo JS|
|Title||Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein.|
|Date||2008 Feb 15|
|Abstract Text||Genes regulated by cyclic AMP-response element-binding protein (CREB) have been reported to suppress apoptosis, induce cell proliferation, and mediate inflammation and tumor metastasis. However, it is not clear whether CREB is critically involved in lung carcinogenesis. We found that non-small cell lung cancer (NSCLC) cell lines exhibited elevated constitutive activity in CREB, in its immediate upstream kinases (ribosomal s6 kinase and extracellular signal kinase), and in the CREB-regulated cell survival proteins Bcl-2 and Bcl-xL. We hypothesized that constitutively active CREB is important to lung cancer cell growth and survival and therefore could be a potential therapeutic target for NSCLC. Ectopic expression of dominant repressor CREB and transfection with small interfering RNA against CREB suppressed the growth and survival of NSCLC cells and induced apoptotic cell death. Furthermore, treating H1734 NSCLC cells with an inhibitor of the CREB signaling pathway Ro-31-8220 inhibited CREB activation by blocking the activity of extracellular signal kinase and ribosomal s6 kinase, arrested the cell cycle at the G(2)-M phase, and subsequently induced apoptosis with the suppression of Bcl-2 and Bcl-xL expression. Ro-31-8220 suppressed both the anchorage-dependent and independent growth of NSCLC cells, but its cytotoxic effect was much less prominent in normal bronchial epithelial cells. Our results indicate that active CREB plays an important role in NSCLC cell growth and survival. Thus, agents that suppress CREB activation could have potential therapeutic value for NSCLC treatment.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Ro 31-8220||Ro-31-8220|Ro 318220||GSK-3beta Inhibitor 4 PKC Inhibitor (Pan) 10||Ro 31-8220 is a pan-protein kinase C (PKC) inhibitor, with additional activity against additional kinases including GSK3-beta, which may increase apoptosis and decrease growth of tumor cells (PMID: 8373348, PMID: 10998351, PMID: 18281471).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||lung non-small cell carcinoma||not applicable||Ro 31-8220||Preclinical - Cell culture||Actionable||In a preclinical study, Ro 31-8220 decreased CREB signaling, and induced apoptosis and inhibited growth of non-small cell lung cancer cells in culture (PMID: 18281471).||18281471|