Oncotarget

Research Papers:

Crosstalk between the IGF-1R/AKT/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor

Batzaya Davaadelger, Lei Duan, Ricardo E. Perez, Steven Gitelis and Carl G. Maki _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:27511-27526. https://doi.org/10.18632/oncotarget.8484

Metrics: PDF 2030 views  |   HTML 2913 views  |   ?  


Abstract

Batzaya Davaadelger1, Lei Duan1, Ricardo E. Perez1, Steven Gitelis2, Carl G. Maki1

1Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA

2Section of Orthopedic Oncology, Department of Orthopedic Surgery, Rush University, Medical Center, Chicago, IL, USA

Correspondence to:

Carl G. Maki, e-mail: [email protected]

Keywords: p53, p27, IGF-1R/AKT/mTORC1, cisplatin

Received: January 08, 2016     Accepted: March 18, 2016     Published: March 30, 2016

ABSTRACT

The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is aberrantly activated in multiple cancers and can promote proliferation and chemotherapy resistance. Multiple IGF-1R inhibitors have been developed as potential therapeutics. However, these inhibitors have failed to increase patient survival when given alone or in combination with chemotherapy agents. The reason(s) for the disappointing clinical effect of these inhibitors is not fully understood. Cisplatin (CP) activated the IGF-1R/AKT/mTORC1 pathway and stabilized p53 in osteosarcoma (OS) cells. p53 knockdown reduced IGF-1R/AKT/mTORC1 activation by CP, and IGF-1R inhibition reduced the accumulation of p53. These data demonstrate positive crosstalk between p53 and the IGF-1R/AKT/mTORC1 pathway in response to CP. Further studies showed the effect of IGF-1R inhibition on CP response is dependent on p53 status. In p53 wild-type cells treated with CP, IGF-1R inhibition increased p53s apoptotic function but reduced p53-dependent senescence, and had no effect on long term survival. In contrast, in p53-null/knockdown cells, IGF-1R inhibition reduced apoptosis in response to CP and increased long term survival. These effects were due to p27 since IGF-1R inhibition stabilized p27 in CP-treated cells, and p27 depletion restored apoptosis and reduced long term survival. Together, the results demonstrate 1) p53 expression determines the effect of IGF-1R inhibition on cancer cell CP response, and 2) crosstalk between the IGF-1R/AKT/mTORC1 pathway and p53 and p27 can reduce cancer cell responsiveness to chemotherapy and may ultimately limit the effectiveness of IGF-1R pathway inhibitors in the clinic.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 8484