Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

Chiang, Ming-Fu; Chou, Pin-Fenn; Wang, Wan Jen; Sze, Chun I.; Chang, Nan Shan

doi:10.3389/fonc.2013.00043

Cited by 26 publications

(39 citation statements)

References 91 publications

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“…15, 54 The cytoprotective function of DJ-1 is related to its ability to sequester p53, therefore inhibiting the apoptotic p53-Bax-caspase pathway and cell cycle arrest functionality (Figure 1B). 1555 The aforementioned Akt signaling pathway is also influenced by the p53 protein activity.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

et al. 2016

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We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and western immunoblotting analysis, revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNA-mediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinum-resistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion: (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation, migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

et al. 2016

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“…P53 serves as a transcription factor, and has a wide range of functions in cell cycle regulation, cell cycle arrest, DNA repair and apoptosis through transactivation of specific genes in response to DNA damage (ionizing radiation, IR and UV light, chemotherapeutic agents) and other cellular stress signals3233. Previously it was reported that p53 has an impact on the sensitivity of glioma cells to TMZ, ACNU and BCNU93435. Interestingly, in spite of the lack of p53-binding sites in the MGMT promoter, several studies have explored the impact of p53 on MGMT expression363738.…”

Section: Discussionmentioning

confidence: 99%

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Nie

Jin

et al. 2016

Sci Rep

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The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance.

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“…We have demonstrated that both WWOX and p53 function in a synergistic manner in causing apoptosis under various stress conditions. [8][9][10][11][12] Our supporting evidence revealed that NO, nitric oxide synthase 2 (NOS2), p53 and WWOX enhance in the bubbling death, whereas antiapoptotic TRAF2 blocks the cell death. 12 Importantly, nuclear accumulation of p53 and WWOX is needed to activate NOS2 to induce formation of NO.…”

Section: Wwox In Bubbling Deathmentioning

confidence: 92%

“…1,[8][9][10][11][12][13] In our most recent study, we have reported temperature-regulated ''bubbling death'' and its transition with apoptosis. 12 Bubbling death is defined as ''formation of a bubble from the nucleus and release of this swelling bubble to the cell surface that causes cell death''.…”

Section: Wwox In Bubbling Deathmentioning

confidence: 99%

Introduction to a Thematic Issue for WWOX

Chang

2015

Exp Biol Med (Maywood)

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Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.

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Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

Cited by 26 publications

References 91 publications

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Introduction to a Thematic Issue for WWOX

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