Downregulation of Choline Kinase-Alpha Enhances Autophagy in Tamoxifen-Resistant Breast Cancer CellsReportar como inadecuado

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Choline kinase-α Chk-α and autophagy have gained much attention, as they relate to the drug-resistance of breast cancer. Here, we explored the potential connection between Chk-α and autophagy in the mechanisms driving to tamoxifen TAM resistance, in estrogen receptor positive ER+ breast cancer cells BCCs. Human BCC lines MCF-7 and TAM-resistant MCF-7 MCF-7-TAM cells were used. Chk-α expression and activity was suppressed by the transduction of shRNA shChk-α with lentivirus and treatment with CK37, a Chk-α inhibitor. MCF-7-TAM cells had higher Chk-α expression and phosphocholine levels than MCF-7 cells. A specific downregulation of Chk-α by the transduction of shChk-α exhibited a significant decrease in phosphocholine levels in MCF-7 and MCF-7-TAM cells. The autophagy-related protein, cleaved microtubule-associated protein light chain 3 LC3 and autophagosome-like structures were significantly increased in shChk-α-transduced or CK37-treated MCF-7 and MCF-7-TAM cells. The downregulation of Chk-α attenuated the phosphorylation of AKT, ERK1-2, and mTOR in both MCF-7 and MCF-7-TAM cells. In MCF-7 cells, the downregulation of Chk-α resulted in an induction of autophagy, a decreased proliferation ability and an activation of caspase-3. In MCF-7-TAM cells, despite a significant decrease in proliferation ability and an increase in the percentage of cells in the G0-G1 phase of the cell cycle, the downregulation of Chk-α did not induced caspase-dependent cell death and further enhanced autophagy and G0-G1 phase arrest. An autophagy inhibitor, methyladenine 3-MA induced death and attenuated the level of elevated LC3 in MCF-7-TAM cells. Elucidating the interplay between choline metabolism and autophagy will provide unique opportunities to identify new therapeutic targets and develop novel treatment strategies that preferentially target TAM-resistance.

Autor: Hoe Suk Kim , Lianji Tian , Minji Jung, Sul Ki Choi, Yujin Sun, Hyeonjin Kim, Woo Kyung Moon



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