Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is common in many human and murine cancer cells, and its activation leads to cellular transformation. STAT3 pathway inhibitors have been reported to suppress cancer growth. To investigate the antitumor effects of inhibiting the STAT3-mediated signaling cascade in the cancer microenvironment, using a molecular-targeting approach, we focused on the gene associated with retinoid-IFN-induced mortality 19 (GRIM-19). GRIM-19 has been reported to interact physically with STAT3 and inhibit STAT3-dependent signal transduction. We used the nonaarginine (R9)-protein transduction domain (R9-PTD) as a protein carrier to induce high levels of GRIM-19 expression in vitro and in vivo. We generated an R9-PTD-containing GRIM-19 fusion protein (rR9-GRIM19) and successfully induced overexpression in the cytoplasm of cancer cells. Analysis of the expression of downstream molecules of STAT3 confirmed that in vitro rR9-GRIM19 treatment of constitutively activated STAT3 (STAT3c) cancer cells significantly reduced STAT3-dependent transcription. Moreover, intratumoral injections of rR9-GRIM19 in STAT3c cancer-bearing mice significantly suppressed tumor growth. These results suggest that intratumoral injections of rR9-GRIM19 have potential as a novel anticancer therapy in STAT3c cancer due to their ability to inhibit STAT3-mediated signal transduction without major systemic side effects. Mol Cancer Ther; 9(8); 2333-43. ©2010 AACR.

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

“…GRIM-19 suppressed not only tumor growth but also neoangiogenesis (19). Consistent with its tumor-suppressive characteristics, we and others have documented a loss of GRIM-19 expression in a number of primary human cancers of the kidney, colon, brain, prostate, lung, and cervix (19,(44)(45)(46)(47)(48)(49)(50)(51). More recently, we have identified functionally inactivating somatic mutations in GRIM-19 in primary human oral SCCs (16).…”

GRIM-19 Mediated Translocation of STAT3 to Mitochondria is Necessary for TNF Induced Necroptosis.

“…GRIM-19 is selective for STAT3 and is not known to bind the other STAT family members. By binding to nuclear STAT3, GRIM-19 (Kalakonda et al, 2007;Okamoto et al, 2010;Wang et al, 2011). Moreover, there is evidence that the mitochondrial localization of GRIM-19 in and of itself enhances cytokine-induced cytotoxicity.…”

Novel immunotherapeutic approaches to skin cancer treatments using protein transduction technology

“…As reported previously, R9-fusion proteins could be efficiently transduced into all tested cell types in culture, including hematopoietic cells ( Fig. 2A) [27][28][29]. Tunnemann et al also demonstrated similar (cell transduction/cell viability) results with an R9-peptide [30].…”