SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells

Talarico, Cristina; Dattilo, Vincenzo; D’Antona, Lucia; Barone, Agnese; Amodio, Nicola; Belviso, Stefania; Musumeci, Francesca; Abbruzzese, Claudia; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Alcaro, Stefano; Ortuso, Francesco; Florio, Tullio; Paggi, Marco G.; Perrotti, Nicola; Amato, Rosario

doi:10.18632/oncotarget.7520

Cited by 55 publications

(79 citation statements)

References 68 publications

(98 reference statements)

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“…4, panels A and B). In the SI113 treated samples, expression of BCL2, as well as the phosphorylation of p-MDM2 (serine 166) were reduced, consistently with previously published observations [31,35,44], whereas the expression of p53, BECN1 and LC3BI/II was increased, as expected [31,40]. In the 64 CuCl 2 treated cells we only recorded modifications affecting p53, BCL2 and TCR1.…”

Section: Si113/ 64 Cucl 2 and Protein Expression In LI Adf And T98g supporting

confidence: 90%

“…The treated cells were prepared for incubation with 1% BSA. The results include counts and percentages of cells in each of the quadrant-defined populations, as well as the mean fluorescence intensity of Annexin V and 7-AAD for each population [39,40]. …”

Section: Guava Nexin Assaymentioning

confidence: 99%

“…We therefore explored the possibility that SI113-dependent [36,37]. We evaluated the effect of SI113 on 64 CuCl 2 radiosensitivity of LI, ADF and T98G cells 24h after plating.…”

Section: Si113 Potentiates In a Time Dependent Manner The Radiation-imentioning

confidence: 99%

“…Among these molecules, SI113 has been demonstrated to inhibit SGK1 activity, while being much less effective on AKT1, ABL and SRC [35]. SI113 induces cell death, alters the growth rate, promotes autophagy and synergizes with taxanes and radiotherapy in hepatocarcinoma and glioblastoma cells in vitro as well as in vivo, also by favoring a cellular sensibilization to these treatments [35][36][37][38]. Based on the apparent lack of toxicity and the consistent ability of SI113 to negatively modulate the chemo-radio resistance [36], in the present work we investigated the potential combined use of 64 CuCl 2 and SI113 in GBMs cellular models.…”

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confidence: 99%

“…SGK1 is also responsible for proliferative and differentiating processes and allows epigenomic regulation in the cell [27,31,33]. The role of Sgk1 in controlling autophagic processes in tumor systems and response to oxidative stress is also well known [40]. Recently the SGK1 inhibitor, SI113, has shown a potential role in the treatment of several cancers, showing an absence of short-term toxicity.…”

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The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Catalogna

Talarico

Dattilo

et al. 2017

Cell Physiol Biochem

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Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemoradio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64 CuCl 2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64 CuCl 2 . Results: We demonstrate here, that i) 64 CuCl 2 is able to induce a time and dose dependent modulation of cell viability (with different IC 50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64 CuCl 2 in GBM cells.G. Catalogna and C. Talarico equally contributed to this work.

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Section: Si113/ 64 Cucl 2 and Protein Expression In LI Adf And T98g supporting

confidence: 90%

Section: Guava Nexin Assaymentioning

confidence: 99%

“…We therefore explored the possibility that SI113-dependent [36,37]. We evaluated the effect of SI113 on 64 CuCl 2 radiosensitivity of LI, ADF and T98G cells 24h after plating.…”

Section: Si113 Potentiates In a Time Dependent Manner The Radiation-imentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Catalogna

Talarico

Dattilo

et al. 2017

Cell Physiol Biochem

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The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

et al. 2017

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Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long‐lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal‐regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient‐induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL‐induced autophagy and cytotoxicity in HepG2 and MHCC97‐H hepatocellular carcinoma cells. These results imply that the GL‐related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97‐H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97‐H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC.

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The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells

Conza

Mirra

Calı̀

et al. 2017

Journal Cellular Physiology

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Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B-II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase-9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real-Time RT-PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.

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SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells

Cited by 55 publications

References 68 publications

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells

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