肿瘤细胞中自噬抑制的非细胞自主性效应促进耐药细胞生长。
Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells.
作者信息
Thorburn Jacqueline, Staskiewicz Leah, Goodall Megan L, Dimberg Lina, Frankel Arthur E, Ford Heide L, Thorburn Andrew
机构信息
Department. of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (J.T., L.S., M.L.G., L.D., H.L.F., A.T.); and Department of Medicine, University of Texas Southwest Medical School, Dallas, Texas (A.E.F.).
Department. of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (J.T., L.S., M.L.G., L.D., H.L.F., A.T.); and Department of Medicine, University of Texas Southwest Medical School, Dallas, Texas (A.E.F.)
出版信息
Mol Pharmacol. 2017 Jan;91(1):58-64. doi: 10.1124/mol.116.106070. Epub 2016 Nov 9.
Autophagy, the mechanism by which cells deliver material to the lysosome, has been associated with resistance to anticancer drugs, leading autophagy inhibition to be widely studied as a potential chemosensitization strategy for cancer cells. This strategy is based on the idea that inhibition of autophagy will increase drug sensitivity and kill more cancer cells. Here we report an unintended negative effect of this strategy. When modeling the effect of drug resistance in a heterogeneous cancer cell population, we found that autophagy inhibition in drug-sensitive tumor cells causes increased growth of drug-resistant cells in the population through a mechanism involving caspase activation and prostaglandin E signaling. These results emphasize the importance of understanding how autophagy manipulation in a tumor cell can have both cell-autonomous and nonautonomous effects and suggest that attempts to chemosensitize by inhibiting autophagy could be enhanced by adopting methods aimed at reducing tumor repopulation.
自噬是细胞将物质输送到溶酶体的机制，它与抗癌药物耐药性有关，这使得自噬抑制作为一种潜在的癌细胞化学增敏策略得到广泛研究。该策略基于这样一种观点，即抑制自噬会增加药物敏感性并杀死更多癌细胞。在此，我们报告了该策略一个意想不到的负面影响。在对异质性癌细胞群体中的耐药性效应进行建模时，我们发现，药物敏感肿瘤细胞中的自噬抑制会通过一种涉及半胱天冬酶激活和前列腺素E信号传导的机制，导致群体中耐药细胞的生长增加。这些结果强调了理解肿瘤细胞中自噬调控如何产生细胞自主和非自主效应的重要性，并表明通过采用旨在减少肿瘤再增殖的方法，可以增强抑制自噬来实现化学增敏的尝试。
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