Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

Elife. 2016 Apr 12:5:e13446. doi: 10.7554/eLife.13446.

Abstract

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

Keywords: bone cancer; cell biology; developmental biology; human; mouse; osteoblast; osteosarcoma; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteosarcoma / genetics*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Parathyroid Hormone-Related Protein / genetics*
  • Parathyroid Hormone-Related Protein / metabolism
  • Primary Cell Culture
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Parathyroid Hormone-Related Protein
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Cyclic AMP

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.