The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer

Aljabery, Firas; Shabo, Ivan; Gimm, Oliver; Jahnson, Staffan; Olsson, Hans

doi:10.1016/j.urolonc.2018.05.025

Cited by 19 publications

(17 citation statements)

References 34 publications

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“…Mutations in TP53 are associated with a worse prognosis in urinary bladder tumors (Aljabery et al ., 2018). Although silibinin selectivity for urinary bladder tumor cells is known (Tyagi et al ., 2007; Zeng et al ., 2011), until now the molecular effects in cells with different TP53 gene status were not well understood.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC).In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status.

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Section: Discussionmentioning

confidence: 99%

Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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“…Biomarkers that underline the effect of a therapeutic approach based on the induction of senescence have to be evaluated carefully and quite often simultaneously. The investigation of senescence markers after post-operative chemotherapy in muscle-invasive bladder cancer (MIBC) revealed that the simultaneous expression of several markers involved in the p53 pathway has to be checked to correctly assess the pathological outcome of MIBC ( 509 ). The analysis revealed that the expression of p14 (Arf) was associated with an impaired response to chemotherapy and poor prognosis, whereas p21 (Waf1) expression was related to reduced tumor cell proliferation ( 509 ).…”

Section: The Escape Of Cancer Stem Cells From Therapymentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

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“…The overexpression of p21 can sensitize cancerous cells to apoptosis[22]. The expression of p21 is positively related to decreased proliferation in cancerous cells[23].…”

Section: Introductionmentioning

confidence: 99%

Brucea javanica oil emulsion improves the effect of radiotherapy on esophageal cancer cells by inhibiting cyclin D1-CDK4/6 axis

Qiu

Zhang

et al. 2019

WJG

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BACKGROUND Esophageal cancer is one of the most common cancers around the world, and it has high incidence and mortality rates. The conventional therapy for esophageal cancer is radiotherapy, although its effect is highly limited by the resistance of esophageal cancer cells. Thus, strong radiosensitizers can be very crucial during radiotherapy against esophageal cancer. Brucea javanica oil emulsion (BJOE) is a widely used drug against various cancers, such as liver, colon, and ovarian cancer. However, its anti-cancer effect and mechanism and the use of BJOE as a radiosensitizer have not been explored in esophageal cancer. AIM To evaluate the anti-cancer effect and mechanism of BJOE and explore the potential use of BJOE as a radiosensitizer during radiotherapy. METHODS The inhibitory effect of BJOE and its enhancement function with radiation on cell viability were examined with the calculated half-maximal effective concentration and half-maximal lethal concentration. The influence of BJOE on cell migration and invasion were measured with EC109 and JAR cells by wound-healing and transwell assay. Clonogenesis and apoptotic rate, which was measured by Hoechst staining, were investigated to confirm its enhancement function with radiation. To investigate the molecular pathway underlying the effect of BJOE, the expressions of several apoptosis- and cycle-related proteins was detected by western blotting. RESULTS Our results demonstrated that BJOE inhibited the growth of esophageal cancer cell lines more than normal cell lines, and it markedly reduced migration and invasion in esophageal cancer cells (EC109 and JAR). Moreover, it promoted cell apoptosis and enhanced the effect of radiotherapy against esophageal cancerous cells. In the viability test, the values of half-maximal effective concentration and half-maximal lethal concentration were reduced. Compared to the control, only around 1/5 colonies formed when using BJOE and radiation together in the clonogenic assay. The apoptotic rate in EC109 was obviously promoted when BJOE was added during radiotherapy. Our study suggests that the expression of the apoptosis-proteins Bax and p21 were increased, while the expression of Bcl-2 was stable. Further detection of downstream proteins revealed that the expression of cyclin D1 and cyclin-dependent kinase 4/6 were significantly decreased. CONCLUSION BJOE has a strong anti-cancer effect on esophageal cancer and can be used as a radiosensitizer to promote apoptosis in cancerous esophageal cells via the cyclin D1-cyclin-dependent kinase 4/6 axis.

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The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer

Cited by 19 publications

References 34 publications

Inhibition of urinary bladder cancer cell proliferation by silibinin

Inhibition of urinary bladder cancer cell proliferation by silibinin

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Brucea javanica oil emulsion improves the effect of radiotherapy on esophageal cancer cells by inhibiting cyclin D1-CDK4/6 axis

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