Activation of PTEN lipid phosphatase function in lung cancer
Poster Feb 14, 2017
Emily Palumbo, Peng Teng, Prerna Malaney, Michael Kemp, Zhi Tian, Diane Allen-Gipson, Yu Chen, Jianfeng Cai, Vrushank Dave
The low frequency of mutations in tumor suppressor PTEN undermines its role in lung cancer. Instead, PTEN expression/function is often reduced in lung tumors via several non-genomic mechanisms, resulting in hyper-activation of the oncogenic PI3K/AKT pathway. Kinase inhibitor (KI) therapy remains challenging due to off-target effects and generation of alternative signaling cascades following treatment. Direct activation of PTEN phosphatase activity represents a novel alternative therapeutic paradigm to attenuate PI3K/AKT signaling. Herein, we identify and characterize peptidomimetics that enhance PTEN lipid phosphatase activity and attenuate PI3K/AKT pathway signaling. Further, select compounds reduced proliferation, migration and induced cell cycle arrest in lung cancer cells, thereby acting as anticancer agents. We have also elucidated optimal PTEN-peptidomimetic interactions in silico. In summary, we have discovered novel small molecule compounds that directly induce PTEN function and antagonize PI3K/AKT pathway activity in lung cancer cells.
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