Slug Promotes Survival during Metastasis through Suppression of Puma-Mediated Apoptosis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-07, Vol.74 (14), p.3695-3706
• Main Authors: SEAHO KIM, JIAHONG YAO, MACIAN, Fernando, NORTON, Larry, HAZAN, Rachel B, SUYAMA, Kimita, XIA QIAN, QIAN, Bin-Zhi, BANDYOPADHYAY, Sanmay, LOUDIG, Olivier, DE LEON-RODRIGUEZ, Carlos, ZHEN NI ZHOU, SEGALL, Jeffrey
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Cell Line, Tumor; Cell Movement - genetics; Cell Survival - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms - secondary; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - pathology; Pharmacology. Drug treatments; Receptors, Fibroblast Growth Factor - metabolism; RNA Interference; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-2591

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.