Inhibition of nonsense-mediated decay rescues functional p53β/γ isoforms in MDM2-amplified cancers

ABSTRACTCommon mechanisms for p53 loss in cancer include expression of MDM2 or the human papilloma virus (HPV)-encoded E6 protein which both mediate degradation of wild-type (WT) p53 (p53α). Here, we show that two alternatively-spliced, functional, truncated isoforms of p53 (p53β and p53γ, containing exons 1-9 of the p53 gene) can be markedly upregulated by pharmacologic or genetic inhibition of nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. These isoforms lack the MDM2 binding domain and hence have reduced susceptibility to MDM2-mediated degradation. In MDM2-overexpressing cells bearing wildtype TP53 gene, NMD blockade increased p53β/γ expression and p53 pathway activation, enhanced radiosensitivity, and inhibited tumor growth. A similar pattern was observed in HPV+ cancer cells and in cancer cells with p53 mutations downstream of exon 9. These results identify a novel therapeutic strategy for restoration of p53 function in tumors rendered p53 deficient through MDM2 overexpression, HPV infection, or certain p53 mutations.

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p53 Alterations Predict Tumor Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Prospective Series

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.7.1465 ◽

2000 ◽

Vol 18 (7) ◽

pp. 1465-1473 ◽

Cited By ~ 127

Author(s):

Arnauld Cabelguenne ◽

Hélène Blons ◽

Isabelle de Waziers ◽

Françoise Carnot ◽

Anne-Marie Houllier ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Neoadjuvant Chemotherapy ◽

Cell Carcinoma ◽

Head And Neck ◽

P53 Gene ◽

P53 Mutations ◽

P53 Antibodies ◽

Response To Chemotherapy ◽

P53 Status ◽

Response To Neoadjuvant Chemotherapy

PURPOSE: The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance. PATIENTS AND METHODS: In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy. RESULTS: Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P < .001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P < .04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P = .003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy. CONCLUSION: This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.

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Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000056 ◽

2014 ◽

Vol 24 (2) ◽

pp. 218-225 ◽

Cited By ~ 5

Author(s):

Angeles Alvarez Secord ◽

Deanna Teoh ◽

Jingquan Jia ◽

Andrew B. Nixon ◽

Lisa Grace ◽

...

Keyword(s):

Ovarian Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Combination Index ◽

Chemotherapeutic Agents ◽

Cytotoxic Agents ◽

Ovarian Cancer Cells ◽

Response Curves ◽

Pathway Activation ◽

Skov3 Cells

PurposeThis study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.MethodsCells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.ResultsIn the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).ConclusionsDasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

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A newly developed adenovirus-mediated transfer of a wild-type p53 gene increases sensitivity to cis-diamminedichloroplatinum (II) in p53-deleted ovarian cancer cells

European Journal of Cancer ◽

10.1016/s0959-8049(98)00199-3 ◽

1998 ◽

Vol 34 (11) ◽

pp. 1802-1806 ◽

Cited By ~ 17

Author(s):

Y Kanamori ◽

J Kigawa ◽

Y Minagawa ◽

T Irie ◽

T Oishi ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

P53 Gene ◽

Ovarian Cancer Cells ◽

Wild Type ◽

Wild Type P53

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Capsular polysaccharide from a fish-gut bacterium induces/promotes apoptosis of colon cancer cells in vitro through Caspases' pathway activation

Carbohydrate Polymers ◽

10.1016/j.carbpol.2021.118908 ◽

2021 ◽

pp. 118908

Author(s):

Rossella di Guida ◽

Angela Casillo ◽

Antonietta Stellavato ◽

Soichiro Kawai ◽

Takuya Ogawa ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Capsular Polysaccharide ◽

Colon Cancer Cells ◽

Pathway Activation ◽

Fish Gut

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Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

Cancer Gene Therapy ◽

10.1038/sj.cgt.7700727 ◽

2004 ◽

Vol 11 (8) ◽

pp. 547-554 ◽

Cited By ~ 16

Author(s):

Sven R Quist ◽

Shan Wang-Gohrke ◽

Tanja Köhler ◽

Rolf Kreienberg ◽

Ingo B Runnebaum

Keyword(s):

Ovarian Cancer ◽

Gene Therapy ◽

Cancer Cells ◽

P53 Gene ◽

Cooperative Effect ◽

Ovarian Cancer Cells ◽

Standard Chemotherapy ◽

P53 Status

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WAF1 expression is independent of p53 gene alterations and protein expression in human lung cancer cells

International Journal of Oncology ◽

10.3892/ijo.9.3.405 ◽

1996 ◽

Author(s):

T Mukhopadhyay ◽

J Roth

Keyword(s):

Lung Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Human Lung ◽

P53 Gene ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Human Lung Cancer Cells ◽

Gene Alterations

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Improved potency of F10 relative to 5-fluorouracil in colorectal cancer cells with p53 mutations

10.20517/cdr.2018.01 ◽

2018 ◽

Vol 1 (1) ◽

pp. 48-58 ◽

Cited By ~ 4

Author(s):

Anthony Dominijanni ◽

William H. Gmeiner

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

P53 Mutations ◽

Colorectal Cancer Cells

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Widespread alteration of protein autoinhibition in human cancers

10.1101/450296 ◽

2018 ◽

Author(s):

Ashwani Jha ◽

Jennifer M. Bui ◽

Dokyun Na ◽

Jörg Gsponer

Keyword(s):

Cancer Cells ◽

Molecular Mechanisms ◽

Signal Propagation ◽

Genetic Alterations ◽

Missense Mutations ◽

Pathway Activation ◽

Tumorigenic Potential ◽

Significant Enrichment ◽

Cancer Types ◽

Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

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