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

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

  • Oncotarget. 2017 Jul 11;8(28):45470-45483. doi: 10.18632/oncotarget.17566.
Yasuyo Suzuki 1 Yasushi Enokido 2 Kenichiro Yamada 1 Mie Inaba 3 Kumiko Kuwata 4 Naoki Hanada 5 Tsuyoshi Morishita 4 Seiji Mizuno 3 Nobuaki Wakamatsu 1
Affiliations

Affiliations

  • 1 Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
  • 2 Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
  • 3 Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Japan.
  • 4 Department of Plastic and Reconstructive Surgery, Aichi Children's Health and Medical Center, Obu, Japan.
  • 5 Hanada Kodomo Clinic, Okazaki, Japan.
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.

Keywords

PI3-kinase; PIK3CA-related overgrowth spectrum (PROS); heterozygous mosaic mutation; mTOR; metformin.

Figures
Products