Serum and Glucocorticoid Inducible Kinase 1-Sensitive Survival, Proliferation and Migration of Rhabdomyosarcoma Cells

Abstract

Background/Aims: Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, may show an intrinsic refractoriness to standard chemotherapy in advanced tumor stages, which is associated with poor prognosis. Cellular mechanisms conferring tumor cell survival and therapy resistance in many tumor types include the serum & glucocorticoid inducible kinase (SGK) 1 pathway, a kinase expressed ubiquitously with particularly strong expression in skeletal muscle and some tumor types. The present study explored whether SGK1 is expressed in rhabdomyosarcoma and, if so, whether this kinase impacts on tumor cell survival, proliferation and migration. Multiple in vitro techniques were used to study the role of SGK1 in rhabdomyosarcoma. Methods: The Gene Chip® Human Genome U133 Plus 2.0 Array were employed to examine SGK1 transcriptional activity in healthy muscle and rhabdomyosarcoma tissue. SGK1 transcript levels were quantified in rhabdomyosarcoma cell lines RD (embryonal subtype) and RH30 (alveolar subtype) by RT-PCR, cell viability was measured using MTT assays. Clonal cell growth was assessed via colony forming assays and migration experiments were performed in a transwell system. Results: SGK1 is expressed in embryonal and alveolar rhabdomyosarcoma tissue samples and in RD and RH30 rhabdomyosarcoma cell lines. Administration of EMD638683 – an inhibitor specific for SGK1 - decreased viability of RD and RH30 cells, enhanced the effects of the cytotoxic drug doxorubicin leading to reduced migration and decreased cell proliferation. Conclusions: SGK1 is expressed in rhabdomyosarcoma cells where it contributes to survival, therapy resistance, cell proliferation and migration. Thus, SGK1 inhibitors may be considered a therapeutic option for the treatment of therapy-resistant rhabdomyosarcoma.

SGK1 in Human Cancer: Emerging Roles and Mechanisms

“…In most tumor types, the expression of SGK1 is dysregulated, although SGK1 upregulation or downregulation has been differentially observed, subject to the particular tumor type. In solid tumors, SGK1 is often upregulated in most of the cancer, such as adrenocortical adenomas ( 26 ), breast cancer ( 14 ), endometrial cancer ( 30 ), gastric cancer (GC) ( 15 ), lung cancer ( 16 , 17 , 31 ), medulloblastoma ( 32 ), oral squamous cell carcinoma (OSCC) ( 33 ), ovarian cancer ( 34 ), prostate carcinoma ( 20 , 35 ), renal clear cell carcinoma ( 32 ), and rhabdomyosarcoma ( 36 ). Although the exact reason why SGK1 expression in cancer in the intestinal system is downregulated remains unclear ( 24 , 25 ), it has been postulated to most likely be due to transcriptional repressors acting on the SGK1 promoter ( 37 ).…”

“…Isikbay et al ( 45 ) found that SGK1 activation plays a crucial role in GR-mediated CRPC progression through acquired resistance to androgen receptor (AR)-directed therapy. In doxorubicin (DOX)-treated rhabdomyosarcoma, SGK1 was found to often be upregulated and led to a poor prognosis ( 36 ). In addition, SGK1 was detected to play a key role in the development of resistance to cancer chemotherapy in NSCLC patients ( 16 ).…”

“…Consistent with this, it has been reported that SGK1 is essential for the invasion and metastasis of different human cancers ( Figure 1 ). Overexpression of SGK1 significantly promotes cell migration and invasion in various cancers, including breast cancer ( 42 ), lung cancer ( 17 ), colon cancer ( 51 ), glioma ( 71 ), hepatoma ( 71 ), OSCC ( 33 ), prostate cancer ( 20 ), and rhabdomyosarcoma ( 36 ).…”

“…In addition, when exposed to SI113, these cancer cells showed a remarkable subversion of the cytoskeletal architecture, characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolymerization ( 71 ). In addition, administration of EMD638683 - an inhibitor specific for SGK1 - decreased the viability of RD and RH30 cells and enhanced the effects of the cytotoxic drug doxorubicin ( 36 ). We obtained similar results in PCa cells treated with GSK650394 ( 20 ), the first developed inhibitor of SGK ( 49 ).…”

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

“…45 Serum and glucocorticoid inducible kinase expression in RMS has been shown to be associated with treatment resistance in RMS cell lines. 46 In vitro and in vivo studies in RMS have shown that GST mediates chemotherapy resistance. 47…”