副凋亡:肿瘤细胞克服凋亡抵抗的途径（英文）

Paraptosis:a way to overcome apoptotic resistance in cancer cells

Since inherent or acquired cellular resistance to various pro-apoptotic treatments often leads to therapeutic failure,a better understanding of alternative non-apoptotic pathways may facilitate the design of novel therapeutics against malignant cancer cells.Paraptosis is a cell death mode characterized by extensive vacuolization that arises via dilation of the endoplasmic reticulum(ER)and mitochondria,without any apoptotic characteristics.We found that curcumin,dimethoxycurcumin(a more stable analog of curcumin),and celastol kill malignant cancer cells via induction of paraptosis as a main cell death mode.Study on the underlying mechanisms of paraptosis revealed that simultaneous proteasomal inhibition and mitochondrial Ca2+ overload can effectively induce paraptosis in cancer cells.Mitochondrial Ca2+ overload can be achieved not only by inhibition of mitochondrial Na+/Ca2+ exchanger but also by IP3 receptor-or ryanodine receptor-mediated release of Ca2+ from the ER and its subsequent mitochondrial Ca2+ uniporter-mediated Ca2+ influx into mitochondria.Since malignant cancer cells are more vulnerable to oxidative stress and ER stress than normal cells,clarification of the molecular basis of paraptosis that targets mitochondria and the ER at the same time may provide a rational therapeutic strategy for effectively killing resistant cancer cells.