Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma

Yun, Xinwei; Zhang, Keqiang; Wang, Jinhui; Pangeni, Rajendra P.; Yang, Lu; Bonner, Melissa; Wu, Jun; Wang, Jami; Nardi, Isaac K.; Gao, Ming; Raz, Dan J.

doi:10.1158/1541-7786.mcr-18-0042

Cited by 32 publications

(26 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The compound ID (CID) of DDP in PubChem Compound is 441203 ( Figure 1B ). It has been extensively utilized to cure different types of neoplasms, including head and neck ( 9 , 10 ), lung ( 11 , 12 ), ovarian ( 13 , 14 ), breast ( 15 , 16 ), brain ( 17 , 18 ), kidney ( 19 , 20 ), and esophagus cancers ( 21 – 23 ). In general, DDP and other platinum-based compounds are considered to be cytotoxic drugs, which can induce apoptosis of cancer cells ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway

et al. 2020

View full text Add to dashboard Cite

Cisplatin (DDP) represents one of the common drugs used for esophageal squamous cell carcinoma (ESCC), but side effects associated with DDP and drug resistance lead to the failure of treatment. This study aimed to understand whether tanshinone IIA (tan IIA) and DDP could generate a synergistic antitumor effect on ESCC cells. Tan IIA and DDP are demonstrated to restrain ESCC cell proliferation in a time-and dose-dependent mode. Tan IIA and DDP at a ratio of 2:1 present a synergistic effect on ESCC cells. The combination suppresses cell migration and invasion abilities, arrests the cell cycle, and causes apoptosis in HK and K180 cells. Molecular docking indicates that tan IIA and DDP could be docked into active sites with the tested proteins. In all treated groups, the expression levels of E-cadherin, β-catenin, Bax, cleaved caspase-9, P21, P27, and c-Fos were upregulated, and the expression levels of fibronectin, vimentin, Bcl-2, cyclin D1, p-Akt, pERK , p-JNK, P38, COX-2, VEGF, IL-6, NF-κB, and c-Jun proteins were downregulated. Among these, the combination induced the most significant difference. Our results suggest that tan IIA could be a novel treatment for combination therapy for ESCC.

show abstract

Section: Introductionmentioning

confidence: 99%

RETRACTED: Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Therefore, we focused our attention on several of these genes based on the strong activation of their expression in the oncosphere, which was dependent on NUDT5 (Figure 6A). Prostagladin E synthase (PTGES) is known to be associated with an increased risk of breast cancer [46]; focadhesin (FOCAD) is a transmembrane protein of which very little is known, except a putative tumour suppressor role in gliomas [47]; the small GTPase RAB35B has putative oncogenic properties [48] and its inhibition reduces exosome release, tumour growth, CSC and metastasis [49]; the ubiquitin specific peptidase 22 (USP22) has been identified as 1 of 11 known “death from cancer” signature genes [50], promoting lethal tumour progression, being associated with end stage disease and CSC [51,52] and has gained interest as a cancer therapy target [53]. We validated the significant reduction in expression of some of these genes in oncospheres, following the inhibition of NUDT5 by qRT-PCR (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5

Pickup

Pardow

Carbonell-Caballero

et al. 2019

Cancers

View full text Add to dashboard Cite

The growth of cancer cells as oncospheres in three-dimensional (3D) culture provides a robust cell model for understanding cancer progression, as well as for early drug discovery and validation. We have previously described a novel pathway in breast cancer cells, whereby ADP (Adenosine diphosphate)-ribose derived from hydrolysis of poly (ADP-Ribose) and pyrophosphate (PPi) are converted to ATP, catalysed by the enzyme NUDT5 (nucleotide diphosphate hydrolase type 5). Overexpression of the NUDT5 gene in breast and other cancer types is associated with poor prognosis, increased risk of recurrence and metastasis. In order to understand the role of NUDT5 in cancer cell growth, we performed phenotypic and global expression analysis in breast cancer cells grown as oncospheres. Comparison of two-dimensional (2D) versus 3D cancer cell cultures from different tissues of origin suggest that NUDT5 increases the aggressiveness of the disease via the modulation of several key driver genes, including ubiquitin specific peptidase 22 (USP22), RAB35B, focadhesin (FOCAD) and prostagladin E synthase (PTGES). NUDT5 functions as a master regulator of key oncogenic pathways and of genes involved in cell adhesion, cancer stem cell (CSC) maintenance and epithelial to mesenchyme transition (EMT). Inhibiting the enzymatic activities of NUDT5 prevents oncosphere formation and precludes the activation of cancer driver genes. These findings highlight NUDT5 as an upstream regulator of tumour drivers and may provide a biomarker for cancer stratification, as well as a novel target for drug discovery for combinatorial drug regimens for the treatment of aggressive cancer types and metastasis.

show abstract

“…Furthermore, combined inhibition of USP22 and HSP90 may provide an effective combinatorial approach to tumor therapy, which would overcome the context-dependency demonstrated in our studies. Interestingly, it was described that USP22 knockdown sensitized lung adenocarcinoma tumor spheres towards cisplatin treatment 30 . Similarly, Ganetespib-based HSP90 inhibition induced cell death via severe global chromosome fragmentation upon carboplatin treatment in vitro 31 .…”

Section: Discussionmentioning

confidence: 99%

USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer

et al. 2019

View full text Add to dashboard Cite

As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the Ubiquitin-Specific Protease 22 (USP22) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific Usp22 deletions. Mechanistically, we detected a significant reduction of H3K9ac on the HSP90AB1 gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on HSP90AB1 expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in USP22 expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that HSP90AB1 is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.

show abstract

Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma

Cited by 32 publications

References 48 publications

RETRACTED: Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway

RETRACTED: Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway

Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5

USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer

Contact Info

Product

Resources

About