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The novel hypoxia-inducible factor-1? inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

ABSTRACT: HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1?. In this study, IDF-11774 inhibited the accumulation of HIF-1? in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1? accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.

SUBMITTER: Ban HS

PROVIDER: S-EPMC5520894 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

Ban Hyun Seung HS Kim Bo-Kyung BK Lee Hongsub H Kim Hwan Mook HM Harmalkar Dipesh D Nam Miso M Park Song-Kyu SK Lee Kiho K Park Joon-Tae JT Kim Inhyub I Lee Kyeong K Hwang Geum-Sook GS Won Misun M

Cell death & disease 20170601 6

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment supp ...[more]

PMID: 28569777

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Project description:Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1? (HIF-1?) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1? is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1? is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer.Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus ?-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1?-null (KO) cells, respectively. The impact of HIF-1? deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis.Efficient deletion of HIF-1? reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1? led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1? also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells.These results demonstrate that HIF-1? plays a key role in promoting primary mammary tumor growth and metastasis, in part through regulation of TICs. HIF-1? regulates expression of several members of the Notch pathway, CD133 and markers of the basal lineage in mammary tumors. Our results suggest that CD133, which has not been profiled extensively in breast cancer, may be a useful marker of TICs in the PyMT mouse model. These data reveal for the first time that HIF-1? directly regulates breast TIC activity in vivo.

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The novel hypoxia-inducible factor-1? inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

Publications

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

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