Dataset Information

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1?/VEGF signaling pathway.

ABSTRACT: Lately, the HSP90 client serine/threonine kinase STK33 emerged to be required by cancer cells for their viability and proliferation. However, its mechanistic contribution to carcinogenesis is not clearly understood. Here we report that elevated STK33 expression correlates with advanced stages of human pancreatic and colorectal carcinomas. Impaired proliferation and augmented apoptosis associated with genetic abrogation of STK33 were paralleled by decreased vascularization in tumor xenografts. In line with this, ectopic STK33 not only promoted tumor growth after pharmacologic inhibition of HSP90 using structurally divergent small molecules currently in clinical development, but also restored blood vessel formation in vivo. Mechanistic studies demonstrated that HSP90-stabilized STK33 interacts with and regulates hypoxia-driven accumulation and activation of HIF-1? as well as secretion of VEGF-A in hypoxic cancer cells. In addition, our study reveals a putative cooperation between STK33 and other HSP90 client protein kinases involved in molecular and cellular events through which cancer cells ensure their survival by securing the oxygen and nutrient supply. Altogether, our findings indicate that STK33 interferes with signals from hypoxia and HSP90 to promote tumor angiogenesis and tumor growth.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5652794 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway.

Liu Yang Y Steinestel Konrad K Rouhi Arefeh A Armacki Milena M Diepold Kristina K Chiosis Gabriela G Simmet Thomas T Seufferlein Thomas T Azoitei Ninel N

Oncotarget 20170824 44

Lately, the HSP90 client serine/threonine kinase STK33 emerged to be required by cancer cells for their viability and proliferation. However, its mechanistic contribution to carcinogenesis is not clearly understood. Here we report that elevated STK33 expression correlates with advanced stages of human pancreatic and colorectal carcinomas. Impaired proliferation and augmented apoptosis associated with genetic abrogation of STK33 were paralleled by decreased vascularization in tumor xenografts. In ...[more]

PMID: 29100402

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Project description:The aim of the present study was to explore the effects of BRAF-activated non-protein coding RNA (BANCR) on pancreatic microlymphangiogenesis in pancreatic cancer (PC) and its molecular mechanism under hypoxic conditions. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the expression of BANCR in SW1990 and PANC-1 PC cell lines under normoxic and hypoxic conditions. Subsequently, the expression of BANCR in the PC cells was knocked down using small interfering RNAs (siRNAs). Western blotting and RT-qPCR analyses were performed to detect the expression of hypoxia-inducible factor (HIF-1α), VEGF-C and VEGFR-3 in the transfected cells. In addition, the transfected PC cells were co-cultured with human lymphatic endothelial cells and the lymphatic microvessel density (MLVD) was detected under normal and hypoxic conditions. Furthermore, HIF-1α expression in the PC cells was knocked down using siRNAs, and VEGF-C and VEGFR-3 mRNA expression in the HIF-1α knockdown cells was detected using RT-qPCR. The results showed that the expression of BANCR in the SW1990 and PANC-1 PC cell lines was significantly higher than that in human pancreatic duct endothelial cells. Additionally, the expression of BANCR was significantly increased in PC cells under hypoxic conditions compared with normoxic conditions. The MLVD of PC cells under hypoxic conditions was significantly higher compared with that under normoxic conditions, and the MLVD in the si-BANCR group was lower than that in the si-NC group, indicating that si-BANCR downregulated MLVD. These results indicate that BANCR positively regulated the expression of HIF-1α in PC cells at the transcriptional and translational levels. Finally, the expression levels of VEGF-C and VEGFR-3 in PC cells were significantly reduced when BANCR or HIF-1α expression was knocked down. In conclusion, the results demonstrate that the expression of BANCR in PC cells was significantly increased under hypoxic conditions and suggest that BANCR promoted tumor cell lymphangiogenesis by upregulating the HIF-1α/VEGF-C/VEGFR-3 pathway, which plays an important role in the process of PC lymph node metastasis.

Dataset Information

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1?/VEGF signaling pathway.

Publications

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway.

Similar Datasets

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