Harnessing the p53-PUMA Axis to Overcome DNA Damage Resistance in Renal Cell Carcinoma

Zhou, Xiaoguang; Tolstov, Yanis; Arslan, Aysenur; Roth, Wilfried; Grüllich, Carsten; Pahernik, Sascha; Hohenfellner, Markus; Duensing, Stefan

doi:10.1016/j.neo.2014.09.012

Cited by 14 publications

(16 citation statements)

References 28 publications

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“…However, p53 could also been silenced in other forms, such as promoter hyper-methylation and post-translational modifications [24], [25]. The p53 post-translational modifications include ubiquitination, phosphorylation, acetylation and methylation, which are tightly relevant to p53 function [26], [27]. Among these, ubiquitination was firstly discovered and mostly studied.…”

Section: Discussionmentioning

confidence: 99%

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Yang

Wang

et al. 2017

Neoplasia

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The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines. Further experiment revealed that SHARPIN could facilitate p53 poly-ubiquitination and degradation in MDM2 dependent manner. Immuno-precipitation assay showed that SHARPIN associated with MDM2 and prolonged MDM2 protein stability. Analysis of public available database showed SHARPIN correlated with poor prognosis specifically in p53 wild-type breast cancer patients. Together, our finding revealed a novel modifier for p53/MDM2 complex and suggested SHARPIN as a promising target to restore p53 function in breast cancer.

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Section: Discussionmentioning

confidence: 99%

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Yang

Wang

et al. 2017

Neoplasia

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“…However, in various cells, including renal cancer cells, p53 can also function as an anti-apoptotic protein [31,32,33]. In renal tumours increased p53 expression is associated with metastasis and worse prognosis [34,35,36,37], while siRNA-mediated silencing of TP53 in renal cancer cells, and sensitizes them to apoptosis induced by chemotherapeutic agents [38]. …”

Section: Discussionmentioning

confidence: 99%

“…Notably, the expression of antiapoptotic survivin is not changed by SRSF2 silencing. Finally, decreased expression of SRSF2 results in upregulation of TP53 , which inhibits apoptosis in renal cancer cells [38,39,40,41,52]. …”

Section: Figurementioning

confidence: 99%

Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

Kędzierska

Popławski

Hoser

et al. 2016

IJMS

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Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability.

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“…p53 is reported to be a tumor suppressor protein involved in DNA repair, cell cycle arrest, senescence and apoptosis (15,17). In the present study, Caki-1 and OS-RC-2 RCC cell lines, which contain wild type p53, were used as a cell model (18). The present results demonstrated that the expression of p53 is increased following combined treatment with temsirolimus and curcumin in Caki-1 and OS-RC-2 cells for 48 h. However, this effect is not observed following treatment with temsirolimus or curcumin alone.…”

Section: Discussionmentioning

confidence: 99%

Curcumin enhances temsirolimus-induced apoptosis in human renal carcinoma cells through upregulation of YAP/p53

Zheng

Fan

et al. 2016

Oncology Letters

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Curcumin has frequently been used as a therapeutic agent in the treatment of various types of disease and is known to enhance the drug sensitivity of cells. In the present study, the combined effect of curcumin and temsirolimus treatment on apoptosis in human renal cell carcinoma (RCC) cells was investigated. Temsirolimus is an inhibitor of the mechanistic target of rapamycin signaling pathway and used in the first-line treatment of metastatic RCC. It was demonstrated that curcumin combined with temsirolimus markedly induced apoptosis in RCC cells, however this effect was not observed following curcumin or temsirolimus treatment alone. Co-treatment with temsirolimus and curcumin led to the activation of cleaved poly ADP-ribose polymerase and caspase 3, upregulation of p53 expression and nuclear translocation, and downregulation of B-cell lymphoma 2 protein expression. Furthermore, curcumin treatment was demonstrated to increase Yes-associated protein (YAP) expression in a time-dependent manner, which was concurrent with the curcumin-induced expression pattern of p53 after 2 h. In addition, knockdown of YAP by small interfering RNA caused the attenuation of curcumin-induced increased p53 expression in RCC cells. In conclusion, the present results indicate that combined curcumin and temsirolimus treatment has a synergistic effect on apoptosis in human RCC cells, through the activation of p53. Mechanistically, YAP is essential in the induction of p53 expression by curcumin. Furthermore, the results suggest that pre-treatment or co-treatment of cells with low concentration curcumin enhances the response to targeted drugs, and this presents a potentially novel and efficient strategy to overcome drug resistance in human RCC.

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Harnessing the p53-PUMA Axis to Overcome DNA Damage Resistance in Renal Cell Carcinoma

Cited by 14 publications

References 28 publications

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

Curcumin enhances temsirolimus-induced apoptosis in human renal carcinoma cells through upregulation of YAP/p53

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