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.
Highlights
The IGF-1R/ionizing radiation (IR)/AKT/mTORC1 pathway is aberrantly activated in multiple cancer types and can promote and/ or regulate proliferation and chemotherapy resistance [1,2,3,4,5,6]
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 limit the effectiveness of IGF-1R pathway inhibitors in the clinic
The results indicate that CP induces pAKT(S473) in MHM cells via IGF-1R/IR and not EGFR activation
Summary
The IGF-1R/IR/AKT/mTORC1 pathway is aberrantly activated in multiple cancer types and can promote and/ or regulate proliferation and chemotherapy resistance [1,2,3,4,5,6]. Ligands IGF1 and IGF2 bind the receptor IGF-1R stimulating its auto-phosphorylation on tyrosines This leads to recruitment/activation of adaptor proteins (e.g. IRS1). The mTORC1 kinase complex is activated downstream of AKT and promotes survival, metabolism, growth, and protein synthesis/translation by phosphorylation of substrates (e.g. S6K) [10, 11]. Multiple inhibitors of the IGF1R/IR/AKT/mTORC1 pathway have been developed and are in various phases of clinical testing [14,15,16,17]. While these inhibitors have shown promise in pre-clinical studies they have largely failed to increase long-term patient survival [14, 16, 17]. The reason(s) for the disappointing clinical effect of IGF-1R/IR/AKT/mTORC1 inhibitors is not fully understood
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