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

Oncogene volume 34, pages 5626–5634 (2015)Cite this article

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Abstract

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.

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Acknowledgements

We are indebted to Dr Janet Price for providing the MDA-MB-435-LvBr1 cell line. We also thank Dr Caroline Alexander and members of the Cryns lab for their critical reading of the manuscript. Breast Cancer Research Foundation (VLC and WJG), Susan G. Komen for the Cure Postdoctoral Fellowship Award (DM and VP) and P30CA014520 University of Wisconsin Comprehensive Cancer Center core facility support.

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Authors and Affiliations

  1. Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    D Malin, E Strekalova, V Petrovic, H Rajanala, B Sharma & V L Cryns

  2. Center for Developmental Therapeutics, Northwestern University, Evanston, IL, USA

    A Ugolkov

  3. Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    W J Gradishar

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  1. D Malin
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Correspondence to V L Cryns.

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Malin, D., Strekalova, E., Petrovic, V. et al. ERK-regulated αB-crystallin induction by matrix detachment inhibits anoikis and promotes lung metastasis in vivo. Oncogene 34, 5626–5634 (2015). https://doi.org/10.1038/onc.2015.12

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