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

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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.

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Mannu K Walia

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Patricia MW Ho

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Scott Taylor

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Alvin JM Ng

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Ankita Gupte

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Alistair M Chalk

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Andrew CW Zannettino

Myeloma Research Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
T John Martin

St. Vincent's Institute of Medical Research, Fitzroy, Australia

Competing interests
The authors declare that no competing interests exist.
Carl R Walkley

St. Vincent's Institute of Medical Research, Fitzroy, Australia

For correspondence
cwalkley@svi.edu.au

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Health and Medical Research Council, Australia and the Bureau of Animal Welfare, Victorian Government . All of the animals were handled according to approved institutional animal care and use committee (Animal Ethics Committee) protocols (#017/15) of the St. Vincent's Hospital Melbourne.

Human subjects: Primary human osteoblasts were isolated from bone marrow aspirates from the posterior iliac crest of de-identified healthy human adult donors with informed consent and consent to publish (IMVS/SA Pathology normal bone marrow donor program RAH#940911a, Adelaide, South Australia).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.