Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth

Abstract

Chondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the inability of IDH to convert isocitrate into α-ketoglutarate (α-KG). Instead, α-KG is reduced into D-2-hydroxyglutarate (D-2HG), an oncometabolite. IDH mutations and D-2HG are thought to contribute to tumorigenesis due to the role of D-2HG as a competitive inhibitor of α-KG-dependent dioxygenases. However, the function of IDH mutations in chondrosarcomas has not been clearly defined. In this study, we knocked out mutant IDH1 (IDH1mut) in two chondrosarcoma cell lines using the CRISPR/Cas9 system. We observed that D-2HG production, anchorage-independent growth, and cell migration were significantly suppressed in the IDH1mut knockout cells. Loss of IDH1mut also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1mut knockout cells revealed downregulation of several integrin genes, including those of integrin alpha 5 (ITGA5) and integrin beta 5 (ITGB5). We further demonstrated that deregulation of integrin-mediated processes contributed to the tumorigenicity of IDH1-mutant chondrosarcoma cells. Our findings showed that IDH1mut knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1mut inhibitors for chondrosarcomas that harbor this mutation.

A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

“…Reprogramming of energy metabolism and evading immune destruction are two emerging hallmarks of cancer, providing new insights for cancer therapy [21]. With the recent discovery of specific mutations in metabolic enzymes in certain cancer types, metabolic pathway are increasingly considered as source of new targets [22]. Meanwhile, treatment of cancer has been revolutionized by immunotherapy with currently widely used checkpoint inhibitors against regulatory immune checkpoint molecules.…”

“…Radiation induced cell death releases intracellular adenosine into the extracellular environment, and also releases ATP, which can be hydrolyzed into adenosine via CD39/CD73 pathway [26]. On the other hand, radiation can activate DNA repair, which is an energy-consuming process and finally promote ATP consumption and increase adenosine production [22,27]. Therefore, the enriched adenosine level might result from three aspects: i) direct release of intracellular adenosine, ii) activation of DNA repair and iii) hydrolysis of tumor cell-released ATP via the CD39/CD73 pathway.…”

Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype

“…In ChS, several repetitive point mutations have been described. The most common are mutations in IDH1 and IDH2 genes, which encode isocitrate dehydrogenase 1 and 2, an enzyme that converts isocitrate to α-ketoglutarate (αKG) [ 77 , 78 ]. Somatic mutations of IDH1 and IDH2 result in higher production of 2-hydroxyglutarate (2HG), one of the oncometabolites [ 79 , 80 ] from αKG.…”

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

“…Isocitrate dehydrogenase (IDH) is an important metabolic enzyme in the tricarboxylic acid cycle, whose mutated genes are associated with a variety of tumors, including acute myeloid leukemia (AML), glioma, cholangiocarcinoma, colon cancer and chondrosarcoma (5). IDH mutation can catalyze the conversion of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG) (Figure 1), and studies have found that the level of 2-HG in cancer patients is higher than that in normal or non-mutated cancer patients (6)(7)(8). The increased level of 2-HG and the resulting epigenetic disorders and cell differentiation show the potential carcinogenicity of IDH mutations (9).…”