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

Recent developments in targeting genes and pathways by RNAi‐based approaches in colorectal cancer

“…HIF‐1α is a transcription factor that responds to hypoxia and VEGF is a signaling protein that enhances the growth of new blood vessels. As corroborated with in vitro findings, tumor xenograft experiments on chicken using the chorionallantoic membrane exhibited a strong relationship between reduced proliferation index, as revealed by damaged tumor‐driven vasculature and the number of Ki67 positive tumor cells in vivo 116 …”

Physical plasma-triggered ROS induces tumor cell death upon cleavage of HSP90 chaperone

“…Our recent results show that as less as 1 µM PU-H71 is sufficient to promote cell death as a result of HSP90 inhibition-triggered client degradation 10 , 31 , 32 . In an attempt to mimic sub-liminal drug doses in clinical setup we used for further experiments 50 nM PU-H71.…”

“…Therefore, we sought to involve an HSP90 inhibitor, currently in the clinical trials, in a combined therapy with cold-plasma. Our previous studies showed that treatment of various cancer cells with 0.5 to 1 µM PU-H71 resulted in augmented cell death 10 , 31 , 32 . Here, we pre-incubated MDA-MB-231 breast and SW480 colon cancer cells with as less as 50 nM PU-H71 before plasma intervention.…”

“…These results indicate that cell death following combined plasma and drug treatment is not a lone result of HSP90 cleavage and PKD2 degradation, respectively, as additional molecular mechanisms or molecules likely contribute to this cellular event as well. Investigation of another kinase reported to act as an HSP90 client, namely serine/threonine-kinase 33 (STK33) 31 , 32 , showed that cold-plasma treatment was also associated with STK33 degradation (Suppl. Figs 2B and 3A ).…”

STK33/ERK2 signal pathway contribute the tumorigenesis of colorectal cancer HCT15 cells

“…STK33 overexpression has been observed to take part in angiogenic program in hypoxic tumors [19]. To detect the expression of STK33 in human CRC cell lines and normal cell lines cancer cells, seven different CRC cell lines and two noncancer cell lines were detected by Western blotting.…”