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 αB-
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 αB-
crystallin protein and
messenger RNA (
mRNA) levels. Moreover, we show that ERK inhibition in adherent
cancer cells mimics matrix detachment by increasing αB-
crystallin protein and
mRNA levels, whereas constitutive ERK activation suppresses αB-
crystallin induction during matrix detachment. These findings indicate that ERK inhibition is both necessary and sufficient for αB-
crystallin induction by matrix detachment. To examine the functional consequences of αB-
crystallin induction in anoikis, we stably silenced αB-
crystallin in two different metastatic
carcinoma cell lines. Strikingly, silencing αB-
crystallin increased matrix detachment-induced
caspase activation and apoptosis but did not affect cell viability of adherent
cancer cells. In addition, silencing αB-
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 αB-
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 αB-
crystallin represents a promising molecular target for antimetastatic
therapies.