PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6
Yanlin Yu,
Meng Dai,
Liping Huang,
Weiping Chen,
Ellen Yu,
Arnulfo Mendoza,
Helen Michael,
Chand Khanna,
Marcus Bosenberg,
Martin McMahon,
Glenn Merlino
Affiliations
Yanlin Yu
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Meng Dai
Southern Medical University, Guangzhou, People’s Republic of China
Liping Huang
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Southern Medical University, Guangzhou, People’s Republic of China
Weiping Chen
NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
Ellen Yu
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Arnulfo Mendoza
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Helen Michael
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Chand Khanna
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Marcus Bosenberg
Yale University, New Haven, CT 06520, USA
Martin McMahon
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Glenn Merlino
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Summary: 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 demonstrate 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 indicate that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatment of PTEN mutant melanoma.
