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

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.

Peaceful Living of Tumor Cells with their Non-malignant Neighbors: The trade of tumor cells with Tumor Microenvironment

Tumor cell growth and survival are the outcome of a communication between tumor cells and tumor microenvironment (TME). In another words, tumor cell growth and survival are greatly affected by the interaction between adjacent cells and tumor cells. In this paper, we review the recent advances in studies of TME, including metabolic interplays between tumor cells and their non-malignant neighbors (peaceful interaction and autophagy), trades of signaling pathways (approach to most important ones; cytokine pathway, NF-kB pathway, intra-tumoral hypoxia, oxidative stress, and nitric oxide-depended pathways), miRNAs (as the regulatory molecules which are present in TME), and Tumor-associated Exosomes (TAEs). Characterization of TME bio-molecules, nutrient changes, and cellular and molecular interactions help to clarify progression of cancer, and find novel targets for treatment of cancer.