The p27–Skp2 axis mediates glucocorticoid-induced cell cycle arrest in T-lymphoma cells

Kullmann, Michael; Grubbauer, Claudia; Goetsch, Katrin; Jakel, Heidelinde; Podmirseg, Silvio Roland; Trockenbacher, Alexander; Ploner, Christian; Cato, Andrew C. B.; Weiss, Carsten; Kofler, Reinhard; Hengst, Ludger

doi:10.4161/cc.25622

Cited by 29 publications

(20 citation statements)

References 51 publications

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“…Consistently, upregulation of Skp2 in mice enhanced tumor growth in lymphoma (21), prostate cancer (19) and breast tumor (18). Importantly, high expression of Skp2 has been observed in a wider spectrum of cancers including lymphomas (22,23) (25)(26)(27)(28)(29), prostate (30,31) and gastric cancer (32), melanoma (33)(34)(35), hepatocarcinoma (36) and nasopharyngeal carcinoma (37,38). Skp2 was also highly expressed and was correlated with relapse, metastasis and survival in OS patients (39).…”

Section: Introductionmentioning

confidence: 73%

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Ding

Han

et al. 2017

Oncology Reports

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Abstract. Osteosarcoma (OS) is a common bone tumor that mainly affects children and young adults. S-phase kinase-associated protein 2 (Skp2) has been characterized to play a critical oncogenic role in a variety of human malignancies. However, the biological function of Skp2 in OS remains largely obscure. In the present study, we elucidated the role of Skp2 in cell growth, cell cycle, apoptosis and migration in OS cells. We found that depletion of Skp2 inhibited cell growth in both MG-63 and SW 1353 cells. Moreover, we observed that depletion of Skp2 triggered cell apoptosis in two OS cell lines. Furthermore, downregulation of Skp2 induced cell cycle arrest in the G0/G1 phase in OS cells. Notably, our wound healing assay results revealed that inhibition of Skp2 suppressed cell migration in OS cells. Invariably, our western blot results demonstrated that depletion of Skp2 in OS cells inhibited activation of pAkt and increased p27 expression in OS cells, suggesting that Skp2 exerted its oncogenic function partly through the regulation of Akt and p27. Our findings revealed that targeting Skp2 could be a promising therapeutic strategy for the treatment of OS.

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Section: Introductionmentioning

confidence: 73%

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Ding

Han

et al. 2017

Oncology Reports

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“…A recent publication demonstrated that Dex-induced cell cycle arrest was mediated by the p27-Skp2 axis in Dex-sensitive T-lymphoma cells. 38 Thus, further investigation is required to clarify the mechanism required to initiate Dex-induced cell cycle arrest in Dex-resistant lymphoid malignant cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Jiang

Xie

et al. 2015

Cancer Biology & Therapy

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Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.

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“…A number of studies have revealed that the overexpression of Skp2 is associated with the progression of a variety of types of human cancer (22)(23)(24)(25). Functional deletion of Skp2 leads to stabilization of CDK inhibitors, which can subsequently induce cell-cycle delay or arrest (26,27 The aim of the study was to explore the role of Skp2 in colon carcinoma and to identify whether depletion of Skp2 by Skp2 RNA interference attenuates the proliferation and migration of colon carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Chen¹,

Mo²,

Yu³

et al. 2014

Molecular Medicine Reports

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Abstract. Colon cancer is a common type of malignancy in the digestive system. The aim of the present study was to investigate the role of S-phase kinase-associated protein 2 (Skp2) in colon carcinoma and to identify whether depletion of Skp2 by Skp2-RNA interference (RNAi) attenuates the proliferation and migration of colon carcinoma. Three pairs of small interfering (si)RNA were designed based on the Skp2 gene sequence and the most effective one was used to silence the Skp2 gene in SW620 cells. Subsequent to the interference, quantitative polymerase chain reaction and western blot analysis were used for detecting the expression of Skp-2 mRNA and protein, respectively. The data demonstrated that the Skp2-siRNA effectively inhibited proliferation (P<0.01), increased the levels of apoptosis and induced G 0 /G 1 phase arrest of the SW620 cells (P<0.01). Transfection of the Skp2 siRNA into SW620 cells effectively reduced Skp2 protein levels, while p27 protein levels increased. In the in vivo experiments, a lentiviral vector of the Skp2-RNAi transfected into SW620 cells markedly inhibited Skp2 expression, as detected by immunohistochemical analysis of nude mice. Additionally, tumorigenicity experiments showed that inhibition of Skp2 significantly increased the survival rate of nude mice. Thus, the in vitro and in vivo results demonstrated that interference of Skp2 expression significantly inhibited the proliferation and induced the apoptosis of SW620 cells. This suggests that Skp2 protein has an important role in the progression of colon cancer. Therefore, Skp2 may enable the early diagnosis of colon cancer and provide new insights into molecular targets for cancer therapy.

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The p27–Skp2 axis mediates glucocorticoid-induced cell cycle arrest in T-lymphoma cells

Cited by 29 publications

References 51 publications

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

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