Radiotherapy resistance acquisition in Glioblastoma. Role of SOCS1 and SOCS3

Abstract

Glioblastoma multiforme (GBM) is a poor prognosis type of tumour due to its resistance to chemo and radiotherapy. SOCS1 and SOCS3 have been associated with tumour progression and response to treatments in different kinds of cancers, including GBM. In this study, cell lines of IDH -wildtype GBM from primary cultures were obtained, and the role of SOCS1 and SOCS3 in the radiotherapy response was analysed. Fifty-two brain aspirates from GBM patients were processed, and six new cell lines of IDH -wildtype GBM were established. These new cell lines were characterized according to the WHO classification of CNS tumours. SOCS1 and SOCS3 expression levels were determined, at mRNA level by Q-PCR, at protein level by immunocytochemistry, and Western blot analysis. The results showed that SOCS1 and SOCS3 are overexpressed in GBM, as compared to a non-tumoral brain RNA pool. SOCS1 and SOCS3 expression were reduced by siRNA, and it was found that SOCS3 inhibition increases radioresistance in GBM cell lines, suggesting a key role of SOCS3 in radioresistant acquisition. In addition, radioresistant clonal populations obtained by selective pressure on these cell cultures also showed a significant decrease in SOCS3 expression, while SOCS1 remained unchanged. Furthermore, the induction of SOCS3 expression, under a heterologous promoter, in a radiotherapy resistant GBM cell line increased its radiosensitivity, supporting an important implication of SOCS3 in radiotherapy resistance acquisition. Finally, the treatment with TSA in the most radioresistant established cell line produced an increase in the effect of radiotherapy, that correlated with an increase in the expression of SOCS3 . These effects of TSA disappeared if the increase in the expression of SOCS3 prevented with an siRNA against SOCS3 . Thus, SOCS3 signal transduction pathway (JAK/STAT) could be useful to unmask new putative targets to improve radiotherapy response in GBM.

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

“…However, direct clinical evidence establishing a clear role of TANs in the development of resistance to RT is still lacking. Moreover, it is well established that GBM tumor cells with stemness properties are resistant to RT [48,[68][69][70][71][72]. Infiltrating TANs secrete S100A4 and promote the growth of GSCs and a malignant phenotype, as well as drug resistance, in in vitro and mouse models of GBM [18].…”

Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines

“…Overexpression of IGF-1R has also been associated with a higher tumor grade, inhibition of apoptosis, increased proliferation rate, and angiogenesis in patients with pancreatic ductal adenocarcinoma [ 6 ], and with a lower survival in patients with colorectal cancer [ 7 ]. Moreover, the IGF-1R signaling pathway is highly active in different types of human tumors, as is the case for metastatic melanoma [ 8 ], and is known to play a critical role in the transformation, growth and survival of glioblastoma multiforme (GBM) cells [ 9 , 10 ].…”

Nomogram With a Novel Microenvironment Signature Is Systematically Constructed and Validated to Predict the Survival Rate of Glioma Patients.

“…SOCS3 is related to tumor progression and therapeutic response in glioma, and it crucial for glioma to acquire anti-radioactivity. Hypermethylation of SOCS3 promoter is an important marker of poor prognosis in glioma 24,25 . The expression of SLC47A2 can be cis-regulated in renal cell carcinoma 26 .…”