ERK-regulated alpha B-crystallin induction by matrix detachment inhibits anoikis and promotes lung metastasis in vivo

作者：Malin D; Strekalova E; Petrovic V; Raj****a H; Sharma B; Ugolkov A; Gradishar W J; Cryns V L^*

来源：Oncogene, 2015, 34(45): 5626-5634.

DOI：10.1038/onc.2015.12

Evasion of extracellular matrix detachment-induced apoptosis ('anoikis') is a defining characteristic of metastatic tumor cells. The ability of metastatic carcinoma cells to survive matrix detachment and escape anoikis enables them to disseminate as viable circulating tumor cells and seed distant organs. Here we report that alpha B-crystallin, an antiapoptotic molecular chaperone implicated in the pathogenesis of diverse poor-prognosis solid tumors, is induced by matrix detachment and confers anoikis resistance. Specifically, we demonstrate that matrix detachment downregulates extracellular signal-regulated kinase (ERK) activity and increases alpha B-crystallin protein and messenger RNA (mRNA) levels. Moreover, we show that ERK inhibition in adherent cancer cells mimics matrix detachment by increasing alpha B-crystallin protein and mRNA levels, whereas constitutive ERK activation suppresses alpha B-crystallin induction during matrix detachment. These findings indicate that ERK inhibition is both necessary and sufficient for alpha B-crystallin induction by matrix detachment. To examine the functional consequences of alpha B-crystallin induction in anoikis, we stably silenced alpha B-crystallin in two different metastatic carcinoma cell lines. Strikingly, silencing alpha B-crystallin increased matrix detachment-induced caspase activation and apoptosis but did not affect cell viability of adherent cancer cells. In addition, silencing alpha B-crystallin in metastatic carcinoma cells reduced the number of viable circulating tumor cells and inhibited lung metastasis in two orthotopic models, but had little or no effect on primary tumor growth. Taken together, our findings point to alpha B-crystallin as a novel regulator of anoikis resistance that is induced by matrix detachment-mediated suppression of ERK signaling and promotes lung metastasis. Our results also suggest that alpha B-crystallin represents a promising molecular target for antimetastatic therapies.

• 出版日期2015-11-5
• 单位西北大学