Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer

Xia, Liang; Lan, Chunling; Zhou, Jinzhe; Fu, Wei; Long, Xuesha; An, Yu; Jiao, Guanming; Wang, Kejin; Li, Yongqin; Xu, Jiahong; Huang, Qi; Xu, Bin; Xiao, Junjie

doi:10.7150/jca.19566

Cited by 23 publications

(17 citation statements)

References 26 publications

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“…In colorectal cancer, transfection with a constitutively active SGK1 mutant significantly enhanced cell motility and cell migration via vinculin dephosphorylation ( 51 ). Liang et al ( 48 ) also found that SGK1 overexpression promoted colonic tumor cell migration, while SGK1 shRNA and inhibitors showed the inverse effects ( 72 ). In contrast, Lee et al ( 43 ) showed that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation.…”

Section: Functional Roles Of Sgk1 In Cancermentioning

confidence: 99%

“…We obtained similar results in PCa cells treated with GSK650394 ( 20 ), the first developed inhibitor of SGK ( 49 ). Recently, a new SGK1 inhibitor analog was developed, the GSK650394 analog QGY-5-114-A, which significantly inhibited CRC cell migration in vitro ( 72 ).…”

Section: Functional Roles Of Sgk1 In Cancermentioning

confidence: 99%

“…In light of the emerging evidence highlighting multiple roles for SGK1 in mediating tumorigenesis and progression, several specific and selective inhibitors of SGK1 have been developed, including GSK650394 ( 49 ), EMD638683 ( 140 ), SI113 ( 141 ), QGY-5-114-A ( 72 ), and ZINC00319000 ( 142 ). The mentioned SGK1 inhibitors and their various anti-tumor effects are summarized in Table 2 .…”

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

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SGK1 in Human Cancer: Emerging Roles and Mechanisms

et al. 2021

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Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

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Section: Functional Roles Of Sgk1 In Cancermentioning

confidence: 99%

Section: Functional Roles Of Sgk1 In Cancermentioning

confidence: 99%

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

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SGK1 in Human Cancer: Emerging Roles and Mechanisms

et al. 2021

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“…While combining mTOR with Akt inhibition showed promise with less toxicity, it seems that Akt inhibitor monotherapy had low clinical activity partly due to poor tolerability [322][323][324]. Pre-clinical studies on inhibition of SGK, another target of mTORC2, for the treatment of a variety of cancers are also showing promise [327,328,331]. SGK1 could play a role in enhancing uptake of unsaturated fatty acids in hypoxic lung cancer cell [327].…”

Section: Other Inhibitors Of the Mtor Pathwaymentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

154

108

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…It has been previously reported that phosphorylation of the Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, which are crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis [53]. Activating Integrin β1/FAK and its downstream Src-Syk-STAT3/Akt signaling pathway can promote enhanced cell adhesion and CAM-DR in MM cells [53, 54]. In this study, we have shown that overexpression of Numbl promoted the adhesion of myeloma cells to FN or HS-5 cells via activation of Integrin β1-FAK and the subsequent activation of Akt pathway, which eventually facilitated the survival and drug resistance of myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)

Huang

Cheng

et al. 2019

BMC Cancer

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BackgroundCell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development.MethodsDevelopment of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis.ResultsOur preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells.ConclusionsOur findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

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Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer

Cited by 23 publications

References 26 publications

SGK1 in Human Cancer: Emerging Roles and Mechanisms

SGK1 in Human Cancer: Emerging Roles and Mechanisms

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)

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