Oncotarget

Research Papers:

The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS)

Yasuyo Suzuki, Yasushi Enokido, Kenichiro Yamada, Mie Inaba, Kumiko Kuwata, Naoki Hanada, Tsuyoshi Morishita, Seiji Mizuno and Nobuaki Wakamatsu _

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Oncotarget. 2017; 8:45470-45483. https://doi.org/10.18632/oncotarget.17566

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Abstract

Yasuyo Suzuki1, Yasushi Enokido2, Kenichiro Yamada1, Mie Inaba3, Kumiko Kuwata4, Naoki Hanada5, Tsuyoshi Morishita4, Seiji Mizuno3 and Nobuaki Wakamatsu1

1Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan

2Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan

3Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Japan

4Department of Plastic and Reconstructive Surgery, Aichi Children’s Health and Medical Center, Obu, Japan

5Hanada Kodomo Clinic, Okazaki, Japan

Correspondence to:

Nobuaki Wakamatsu, email: [email protected]

Keywords: PIK3CA-related overgrowth spectrum (PROS), heterozygous mosaic mutation, PI3-kinase, mTOR, metformin

Received: December 21, 2016     Accepted: April 18, 2017     Published: May 02, 2017

ABSTRACT

The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is critical for cellular growth and metabolism. Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). In this study, we report a Japanese female diagnosed with PROS, who presented with hyperplasia of the lower extremities, macrodactyly, multiple lipomatosis, and sparse hair. Sequencing and mutant allele frequency analysis of PIK3CA from affected tissues revealed that the patient had a heterozygous mosaic mutation (c.3140A>G [p.H1047R]) in PIK3CA and that there were higher mutant allele frequencies from samples with a larger amount of subcutaneous adipose tissue. We established two fibroblast cell lines from the patient, harboring high and low frequencies of the mosaic mutation, in which AKT and S6 showed higher level of phosphorylation compared with three control fibroblasts, indicating that PI3K/AKT/mTOR signaling is activated. We assessed the therapeutic effects of four compounds (rapamycin, NVP-BEZ235, aspirin, and metformin) on PI3K/AKT/mTOR signaling pathway and cell growth. All four compounds suppressed S6 phosphorylation and inhibited cell growth of the patient-derived fibroblast cell lines. However, only metformin mildly inhibited the growth of the control fibroblast cell lines. Since PROS is a congenital disorder, drugs for therapy should take into consideration the natural growth of children. Thus, metformin is a candidate drug for treating PROS in growing children.


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