Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis.
Tumor cells must overcome apoptosis to survive throughout metastatic dissemination and distal organ colonization. Here, we show in the Polyoma Middle T mammary tumor model that N-cadherin (Cdh2) expression causes Slug (Snai2) upregulation, which in turn promotes carcinoma cell survival. Slug was dramatically upregulated in metastases relative to primary tumors. Consistent with a role in metastasis, Slug knockdown in carcinoma cells suppressed lung colonization by decreasing cell survival at metastatic sites, but had no effect on tumor cell invasion or extravasation. In support of this idea, Slug inhibition by shRNA sensitized tumor cells to apoptosis by DNA damage, resulting in caspase-3 and PARP cleavage. The prosurvival effect of Slug was found to be caused by direct repression of the proapoptotic gene, Puma (Bbc3), by Slug. Consistent with a pivotal role for a Slug-Puma axis in metastasis, inhibition of Puma by RNA interference in Slug-knockdown cells rescued lung colonization, whereas Puma overexpression in control tumor cells suppressed lung metastasis. The survival function of the Slug-Puma axis was confirmed in human breast cancer cells, where Slug knockdown increased Puma expression and inhibited lung colonization. This study demonstrates a pivotal role for Slug in carcinoma cell survival, implying that disruption of the Slug-Puma axis may impinge on the survival of metastatic cells.
Authors' Affiliations: Departments of Pathology.
Seaho
S
Kim
Authors' Affiliations: Departments of Pathology.
Jiahong
J
Yao
Authors' Affiliations: Departments of Pathology.
Kimita
K
Suyama
Authors' Affiliations: Departments of Pathology.
Xia
X
Qian
Developmental and Molecular Biology, and.
Bin-Zhi
BZ
Qian
Authors' Affiliations: Departments of Pathology.
Sanmay
S
Bandyopadhyay
Authors' Affiliations: Departments of Pathology.
Olivier
O
Loudig
Authors' Affiliations: Departments of Pathology.
Carlos
C
De Leon-Rodriguez
Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx; and.
Zhen Ni
ZN
Zhou
Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx; and.
Jeffrey
J
Segall
Authors' Affiliations: Departments of Pathology.
Fernando
F
Macian
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
Larry
L
Norton
Authors' Affiliations: Departments of Pathology, rachel.hazan@einstein.yu.edu.
Rachel B
RB
Hazan
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D034622:RNA Interference; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D017468:Receptors, Fibroblast Growth Factor; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins