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PTEN phosphatase inhibits metastasis

ABSTRACT: PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We show that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels, while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data show that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatmtreatingwith PTEN mutant melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE210359 | GEO | 2023/03/09

REPOSITORIES: GEO

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Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the ï¡-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Experiment Overall Design: 12 mice were analyzed in this study. Four treatment groups were included in this study: transgenic ATF6-MER mice treated with tamoxifen, transgenic ATF6-MER mice treated with vehicle, nontransgenic littermates treated with tamoxifen, and nontransgenic littermates treated with vehicle. Each treatment group included 3 separate biological replicate samples. Each mouse sampled was male, C57/BL6, ~30 weeks old. Each mouse was treated, then the mouse was sacrificed, the heart was extracted, and left ventricle was isolated. Total RNA was isolated from the left ventricle, and used for hybridization onto an Affymetrix mus 430 2.0 full-genome chip. Each heart was hybridized onto its own chip.

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PTEN phosphatase inhibits metastasis

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