SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition

Talarico, Cristina; Dattilo, Vincenzo; D’Antona, Lucia; Menniti, Miranda; Bianco, Cataldo; Ortuso, Francesco; Alcaro, Stefano; Schenone, Silvia; Perrotti, Nicola; Amato, Rosario

doi:10.1159/000447885

Cited by 75 publications

(69 citation statements)

References 88 publications

(133 reference statements)

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“…Moreover, we found that suppression of miR-124 strikingly reversed XIST knockdownmediated repression on DOX resistance in DOX-resistant CRC cells. SGK1, belonging to the AGC family of serine/threonine protein kinases, has been suggested to be overexpressed and associated with cell proliferation, apoptosis, invasiveness, motility, epithelial to mesenchymal transition, adhesiveness and chemoresistance in a variety of epithelial tumors [20,36]. Amato et al firstly revealed the association of SGK1 and doxorubicin-induced apoptosis in kidney cancer cells [37].…”

Section: Discussionmentioning

confidence: 99%

“…5A, binding sites of miR-124 were identified in the 3'UTR of SGK1 mRNA. SGK1 has been reported to participate in cell survival, de-differentiation, cell cycle control, apoptosis, as well as chemo-and radio-resistance in various malignancies [20]. Moreover, a recent document points out that SGK1 is essential and rate limiting in the control of precursor miRNA nuclear export Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry [21].…”

Section: Xist Positively Regulated Sgk1 Expression By Interacting Witmentioning

confidence: 99%

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Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

Zhu

Zhang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Xist Positively Regulated Sgk1 Expression By Interacting Witmentioning

confidence: 99%

Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

Zhu

Zhang

Yang

et al. 2018

Cell Physiol Biochem

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“…Indeed, this assumption was postulated previously in various tumor cell models by analyzing the correlation of EMT with actin signaling and migration [13, 19-27]. Moreover, previous studies showed that the Serum glucocorticoid kinase 1 (Sgk1) plays a key role in EMT in colon carcinoma [28]. Furthermore, Sgk1 regulates epi-genomic re-alignment and drug-resistance through the control of GTP-proteins RANBP1 and RAN [29].…”

Section: Discussionmentioning

confidence: 86%

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

Zacharopoulou

Tsapara

Kallergi

et al. 2018

Cell Physiol Biochem

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Background/Aims: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. Methods: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins. Results: We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells. Conclusions: These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors.

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“…Both SGK1 and TNFAIP8 reportedly participate in apoptosis evasion, cell survival, chemo resistance and tumor progression (Fig. 5E) (30–33) (34). Western blotting analysis validated select ENZ- and OLA-upregulated pro-apoptotic genes and ENZ-downregulated and OLA-upregulated SGK1 and TNFAIP8 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

et al. 2017

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Cancers with dysfunctional mutations in BRCA1 or BRCA2, most commonly associated with some breast cancers, are deficient in the DNA damage repair pathway called homologous recombination (HR), which makes them exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib. This functional state and therapeutic sensitivity is referred to as “BRCAness”. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only a small proportion of prostate cancer (PCa) patients. We found that castration-resistant PCa (CRPC) cells increased expression of a set of HR-associated genes, including BRCA1, RAD54L and RMI2. Androgen-targeted therapy is typically not effective in CRPC patients. However, the androgen receptor (AR) inhibitor enzalutamide suppressed the expression of those HR genes, thus creating HR deficiency and BRCAness in CRPC cells. In a manner dependent on these gene expression effects, a “lead-in” treatment strategy, in which enzalutamide was followed by the combination of enzalutamide and olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of PCa cells in culture and suppressed the growth of PCa xenografts in mice. Thus, our study suggests that anti-androgen and PARP inhibitor combination therapy may be effective for patients with CRPC, and that pharmaceutically-induced BRCAness may expand the clinical use of PARP inhibitors.

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SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition

Cited by 75 publications

References 88 publications

Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

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