PKM2 Regulates HSP90-Mediated Stability of the IGF-1R Precursor Protein and Promotes Cancer Cell Survival during Hypoxia.

Abstract

Simple SummaryGenerally, IGF-1R is overexpressed in most solid tumors, and its expression is significantly associated with poor prognosis in cancer patients. However, IGF-1R gene amplification events are extremely rare in tumors. It is, therefore, necessary to define the mechanism underlying IGR-1R overexpression to elucidate potential therapeutic targets. Our study, specifically, aimed to define the potential mechanisms associated with PKM2 function in regulating IGF-1R protein expression. PKM2 was found to be a non-metabolic protein that regulates HSP90 binding to and stabilizing the precursor IGF-1R protein, thereby promoting the basal level of mature IGF-1R protein. Consequently, PKM2 knockdown inhibits the activation of AKT, a downstream effector of IGF-1R signaling, and increases apoptosis during hypoxia. Our findings reveal a novel mechanism for regulating IGF-1R protein expression, thus suggesting PKM2 as a potential therapeutic target in cancers associated with aberrant IGF signaling.Insulin-like growth factor-1 receptor (IGF-1R), an important factor in promoting cancer cell growth and survival, is commonly upregulated in cancer cells. However, amplification of the IGF1R gene is extremely rare in tumors. Here, we have provided insights into the mechanisms underlying the regulation of IGF-1R protein expression. We found that PKM2 serves as a non-metabolic protein that binds to and increases IGF-1R protein expression by promoting the interaction between IGF-1R and heat-shock protein 90 (HSP90). PKM2 depletion decreases HSP90 binding to IGF-1R precursor, thereby reducing IGF-1R precursor stability and the basal level of mature IGF-1R. Consequently, PKM2 knockdown inhibits the activation of AKT, the key downstream effector of IGF-1R signaling, and increases apoptotic cancer cell death during hypoxia. Notably, we clinically verified the PKM2-regulated expression of IGF-1R through immunohistochemical staining in a tissue microarray of 112 lung cancer patients, demonstrating a significant positive correlation (r = 0.5208, p < 0.0001) between PKM2 and IGF-1R expression. Together, the results of a previous report demonstrated that AKT mediates PKM2 phosphorylation at serine-202; these results suggest that IGF-1R signaling and PKM2 mutually regulate each other to facilitate cell growth and survival, particularly under hypoxic conditions, in solid tumors with dysregulated IGF-1R expression.