Targeting mutant p53 for cancer therapy

Oren, Moshe; Tal, Perry; Rotter, Varda

doi:10.18632/aging.100992

Cited by 23 publications

(17 citation statements)

References 8 publications

(15 reference statements)

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“…However, contrary to our hypothesis, MDA-MB-231 and MDA-MB-468 cell line endogenously express a mutation in p53 [49]. A mutation in p53 does not function as a tumor suppressor [50, 51]. Additionally, we identified MDM2 protein expression that regulates p53 protein.…”

Section: Discussioncontrasting

confidence: 63%

hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways

et al. 2017

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Breast cancer is the most abundant cancer worldwide and a severe problem for women. Notably, breast cancer has a high mortality rate, mainly because of tumor progression and metastasis. Triple-negative breast cancer (TNBC) is highly progressive and lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Therefore, there are no established therapeutic targets against TNBC. In this study, we investigated whether the expression of human melanoma-associated antigen A2 (MAGEA2) is associated with TNBC. We found that hMAGEA2 is significantly overexpressed in human TNBC tissues; we also observed oncogenic properties using TNBC cell lines (MDA-MB-231 and MDA-MB-468). The overexpression of hMAGEA2 in MDA-MB-231 cell line showed dramatically increased cellular proliferation, colony formation, invasion, and xenograft tumor formation and growth. Conversely, knockdown of hMAEGA2 in MDA-MB-468 cell line suppressed cellular proliferation, colony formation, and xenograft tumor formation. Additionally, we showed that hMAGEA2 regulated the activation of Akt and Erk1/2 signaling pathways. These data indicate that hMAGEA2 is important for progression of TNBC and may serve as a novel molecular therapeutic target.

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Section: Discussioncontrasting

confidence: 63%

hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways

et al. 2017

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“…These tumors usually are more aggressive and resistant to treatment. The compounds that can restore wild type p53 activity have been summarized in several recent reviews [12, 116, 117]. Among all the compounds, PRIMA-1 [2,2-bis (hydroxymethyl)-3-quinuclidinone] is the most well-advanced small molecule [117, 118].…”

Section: Therapeutic Strategies To Target Mutant P53mentioning

confidence: 99%

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Yue

Zhao

et al. 2017

Journal of Molecular Biology

225

203

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Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations. Majority of p53 mutations in cancer are missense mutations, leading to the expression of full-length mutant p53 protein. While the critical role of wild type p53 in tumor suppression has been firmly established, mounting evidence has demonstrated that many tumor-associated mutant p53 proteins not only lose tumor suppressive function of wild type p53, but also gain new activities to promote tumorigenesis independently of wild type p53, termed gain-of-function. Mutant p53 protein often accumulates to very high levels in tumors, contributing to malignant progression. Recently, mutant p53 has become an attractive target for cancer therapy. Further understanding of the mechanisms underlying mutant p53 protein accumulation and gain-of-function will accelerate the development of targeted therapies for human cancer harboring mutant p53. In this review, we summarize the recent advances in the studies on mutant p53 protein accumulation and gain-of-function as well as targeted therapies for mutant p53 in human cancer.

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“…It has been estimated that ~29% of colorectal cancers harbor p53 gene mutations (18). Deficiencies in p53 function attenuate p53-mediated cell apoptosis and may lead to multi-drug resistance (MDR) (19,20). An increasing body of evidence has indicated that p53-mutant or p53-null cancer cells are more likely to be resistant to different cytotoxic drugs; particularly to chemotherapy and radiation therapy in the clinic, as these therapies target cells primarily by inducing apoptosis (19,21).…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane induces p53-deficient SW480 cell apoptosis via the ROS-MAPK signaling pathway

Lan

Yuan

Cai

2017

Molecular Medicine Reports

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Sulforaphane (SFN) has been revealed to inhibit the growth and induce apoptosis of cancer cells. However, the detailed anticancer effects of SFN on p53‑deficient colon cancer cells has yet to be clearly elucidated. The present study employed p53‑deficient SW480 cells to establish an SFN‑induced in vitro model of apoptosis. The critical events leading to apoptosis were then evaluated in SFN‑treated p53‑deficient SW480 cells, by performing an MTT assay, flow cytometry, western blotting and ELISA. The results demonstrated that SFN at concentrations of 5, 10, 15 and 20 µM induced mitochondria‑associated cell apoptosis, which was further confirmed by disruption of the mitochondrial membrane potential, an increase in the Bax/Bcl‑2 ratio, as well as activation of caspase‑3, ‑7 and ‑9. In addition, SFN‑induced apoptosis was associated with an increase in the generation of reactive oxygen species (ROS), and the activation of extracellular signal‑regulated kinases (Erk) and p38 mitogen‑activated protein kinases. However, SFN did not induce expression of the p53 family member, p73. SFN‑induced apoptosis was subsequently confirmed to be ROS‑dependent and associated with Erk/p38, as the specific inhibitors for ROS, phosphorylated (p)‑Erk and p‑p38, completely or partially attenuated the SFN‑induced reduction in SW480 cell viability. In addition, the results demonstrated that even at the lowest concentrations (5 µM), SFN increased the sensitivity of p53‑proficient HCT‑116 cells to cisplatin. In conclusion, the results suggest that SFN may induce apoptosis in p53‑deficient SW480 cells via p53/p73‑independent and ROS‑Erk/p38‑dependent signaling pathways.

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Targeting mutant p53 for cancer therapy

Cited by 23 publications

References 8 publications

hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways

hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways

Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Sulforaphane induces p53-deficient SW480 cell apoptosis via the ROS-MAPK signaling pathway

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