PMID- 25684139
OWN - NLM
STAT- MEDLINE
DCOM- 20160217
LR  - 20170220
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 45
DP  - 2015 Nov 5
TI  - ERK-regulated alphaB-crystallin induction by matrix detachment inhibits anoikis
      and promotes lung metastasis in vivo.
PG  - 5626-34
LID - 10.1038/onc.2015.12 [doi]
AB  - 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 alphaB-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 alphaB-crystallin protein and messenger RNA (mRNA) levels.
      Moreover, we show that ERK inhibition in adherent cancer cells mimics matrix
      detachment by increasing alphaB-crystallin protein and mRNA levels, whereas
      constitutive ERK activation suppresses alphaB-crystallin induction during matrix 
      detachment. These findings indicate that ERK inhibition is both necessary and
      sufficient for alphaB-crystallin induction by matrix detachment. To examine the
      functional consequences of alphaB-crystallin induction in anoikis, we stably
      silenced alphaB-crystallin in two different metastatic carcinoma cell lines.
      Strikingly, silencing alphaB-crystallin increased matrix detachment-induced
      caspase activation and apoptosis but did not affect cell viability of adherent
      cancer cells. In addition, silencing alphaB-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 alphaB-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 alphaB-crystallin represents a promising molecular target for
      antimetastatic therapies.
FAU - Malin, D
AU  - Malin D
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
FAU - Strekalova, E
AU  - Strekalova E
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
FAU - Petrovic, V
AU  - Petrovic V
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
FAU - Rajanala, H
AU  - Rajanala H
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
FAU - Sharma, B
AU  - Sharma B
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
FAU - Ugolkov, A
AU  - Ugolkov A
AD  - Center for Developmental Therapeutics, Northwestern University, Evanston, IL,
      USA.
FAU - Gradishar, W J
AU  - Gradishar WJ
AD  - Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg
      School of Medicine, Northwestern University, Chicago, IL, USA.
FAU - Cryns, V L
AU  - Cryns VL
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University
      of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
LA  - eng
GR  - P30 CA014520/CA/NCI NIH HHS/United States
GR  - P30CA014520/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150216
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Neoplasm Proteins)
RN  - 0 (alpha-Crystallin B Chain)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - *Anoikis
MH  - Breast Neoplasms/genetics/*metabolism/pathology
MH  - Cell Adhesion/genetics
MH  - Cell Line, Tumor
MH  - Extracellular Matrix/genetics/*metabolism/pathology
MH  - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/genetics/*metabolism/pathology/secondary
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Metastasis
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - alpha-Crystallin B Chain/genetics/*metabolism
PMC - PMC4537846
MID - NIHMS653261
EDAT- 2015/02/17 06:00
MHDA- 2016/02/18 06:00
CRDT- 2015/02/17 06:00
PHST- 2014/08/17 00:00 [received]
PHST- 2014/12/11 00:00 [revised]
PHST- 2015/01/02 00:00 [accepted]
PHST- 2015/02/17 06:00 [entrez]
PHST- 2015/02/17 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
AID - onc201512 [pii]
AID - 10.1038/onc.2015.12 [doi]
PST - ppublish
SO  - Oncogene. 2015 Nov 5;34(45):5626-34. doi: 10.1038/onc.2015.12. Epub 2015 Feb 16.