WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation

Líu, Hao; Chen, Wei; Liang, Chao; Chen, Bryan Wei; Zhi, Xu; Zhang, Shufeng; Zheng, Xiaoxiao; Bai, Xueli; Liang, Tingbo

doi:10.1016/j.canlet.2015.03.001

Cited by 55 publications

(47 citation statements)

References 32 publications

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“…It is unquestionable that p53 also plays a crucial role in the drug resistance of various cancers . Thus, we investigated whether SRPK2 regulated drug resistance in a p53‐dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

et al. 2019

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Serine/arginine protein‐specific kinase 2 (SRPK2) plays a vital role in the progression of a range of different malignancies, including pancreatic cancer. However, the mechanisms are poorly understood. Previous studies have shown that in hepatocellular carcinoma, SRPK2 knockdown leads to the upregulation of the cell fate determining protein Numb, and in pancreatic cancer cells, Numb knockdown prevents ubiquitin‐mediated degradation of p53. In this study, we investigated the relationship between SRPK2, Numb and p53 in the development of pancreatic cancer with or without chemical agent treatment in vitro. SRPK2 expression was upregulated in pancreatic cancer tissues and associated with decreased overall survival in pancreatic cancer patients, indicating that expression of this protein can be used as a marker of unfavourable prognosis. Expression of SRPK2 was positively associated with tumour T stage and Union for International Cancer Control (UICC) stage, and negatively associated with Numb expression in serial tissue sections. In pancreatic cancer cells, SRPK2 downregulation or overexpression led to modulation of Numb and wild‐type p53 protein expression in response to oxaliplatin treatment. Furthermore, these three endogenous proteins could be coimmunoprecipitated as a triple complex. Numb or p53 knockdown reversed the upregulation of p53 that was induced by silencing SRPK2. SRPK2 overexpression promoted cell invasion and migration, and decreased chemosensitivity of cancer cells to gemcitabine or oxaliplatin treatment. Conversely, SRPK2 silencing decreased cell invasion and migration and increased chemosensitivity; these effects were reversed by silencing p53 in oxaliplatin‐treated pancreatic cancer cells. Our data suggest that SRPK2 negatively regulates p53 by downregulating Numb under chemical agent treatment. Thus, SRPK2 promotes the development and progression of pancreatic cancer in a p53‐dependent manner.

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Section: Resultsmentioning

confidence: 99%

Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

et al. 2019

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“…It is unquestionable that p53 plays a crucial role in regulating cell cycle arrest, apoptosis, and drug resistance of various cancers (23–25). In the above experiments, wtp53 was found to be the terminal regulated target of MSI2.…”

Section: Resultsmentioning

confidence: 99%

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

et al. 2017

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Our earlier work showed that Musashi (MSI)-2 promoted the development of pancreatic cancer (PC) by down-regulating Numb, which prevented murine double-minute (MDM)-2-mediated p53 ubiquitin degradation. Thus, we investigate the relationship among MSI2, Numb, MDM2, and p53 in PC and, an association that has not been reported to our knowledge. MSI2 had no relationship with mutant p53 (mtp53) and wild-type p53 (wtp53) in normal PC cells. However, in response to gemcitabine or cisplatin treatment, MSI2 silencing simultaneously down-regulated MDM2 and up-regulated Numb and wtp53 protein levels. Moreover, these 4 endogenous proteins can be coimmunoprecipitated as a quaternary complex. Numb small interfering RNA (siRNA) reversed the MSI2 silencing-induced p53 increase. During treatment with chemical agents, MSI2 silencing decreased drug resistance and cell motility and inhibited tumor growth, all of which were significantly reversed by p53 siRNA. MSI2 was also negatively associated with Numb and positively associated with MDM2 expression in tissue. Overexpression of MSI2, MDM2, and mtp53 and weak expression of Numb were closely associated with aggressive clinicopathologic characteristics and poor prognosis for patients with PC. MSI2 negatively regulates wtp53 protein by up-regulating MDM2 and down-regulating Numb after treatment with chemical agents. MSI2 promotes drug resistance and malignant biology of PC in a p53-dependent manner.-Sheng, W., Dong, M., Chen, C., Wang, Z., Li, Y., Wang, K., Li, Y., Zhou, J. Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer.

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“…For example, one recent study showed that inhibiting the deubiquitinase USP9x increased p53 ubiquitination and thus decreased p53 levels, yet it still increased doxorubicin sensitivity in HCC cells. This suggests that the effects of ubiquitination inhibitors are more complex than simply causing the degradation of p53 [53]. Furthermore, increasing p53 is clearly not the only way to enhance doxorubicin sensitivity as the three hepatoma cell lines, Huh7, Hep3B, and HepG2 illustrate.…”

Section: Molecular Mechanisms Of Doxorubicin Resistancementioning

confidence: 99%

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

2015

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Hepatocellular carcinoma, one of the most common solid tumors worldwide, is poorly responsive to available chemotherapeutic approaches. While systemic chemotherapy is of limited benefit, intra-arterial delivery of doxorubicin to the tumor frequently produces tumor shrinkage. Its utility is limited, in part, by the frequent emergence of doxorubicin resistance. The mechanisms of this resistance include increased expression of multidrug resistance efflux pumps, alterations of the drug target, topoisomerase, and modulation of programmed cell death pathways. Many of these effects result from changes in miRNA expression and are particularly prominent in tumor cells with a stem cell phenotype. This review will summarize the current knowledge on the mechanisms of doxorubicin resistance of hepatocellular carcinoma and the potential for approaches toward therapeutic chemosensitization.

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WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation

Cited by 55 publications

References 32 publications

Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

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