The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells

Waye, Sarah; Naeem, Aisha; Choudhry, Muhammad Umer; Parasido, Erika; Tricoli, Lucas; Sivakumar, Angiela; Mikhaiel, John P.; Yenugonda, Venkata Mahidhar; Rodriguez, Olga; Karam, Sana D.; Rood, Brian R.; Avantaggiati, Maria Laura; Albanese, Chris

doi:10.18632/aging.100831

Cited by 16 publications

(20 citation statements)

References 55 publications

(88 reference statements)

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“…In HCT116 colon carcinoma cells treated with oxaliplatin, for example, moderate concentrations that are typically used in the colony formation assay (e.g., <5 μM) [ 68 ] result in significant growth arrest (e.g., determined by the MTS cell proliferation assay) but virtually no apoptosis [ 67 ], whereas >20 μM concentrations of oxaliplatin are required to trigger apoptosis [ 67 ] (also see Figure 2 ). Similar discrepancy between growth-inhibitory and apoptosis-inducing concentrations has been reported for cisplatin (reviewed in [ 66 ] for a large number of cancer cell lines), paclitaxel [ 65 ] and doxorubicin [ 62 , 63 , 64 ]. When examined, moderate (sub-apoptotic) concentrations of these agents trigger a high degree of SIPS [ 66 , 70 , 71 ].…”

Section: Cancer Cell Response To Genotoxic Stress: Reversible Growsupporting

confidence: 71%

“…Numerous studies reported since the 1990s, some from our laboratory [ 53 , 54 , 55 , 56 , 57 ], have established the presence of a threshold mechanism for stress-induced growth arrest versus apoptosis in human cells with different p53 status, with moderate doses of DNA-damaging agents predominantly (if not solely) triggering growth arrest (e.g., SIPS) in some cell types. This threshold effect has been observed for ionizing radiation [ 54 , 55 , 56 , 57 , 58 , 59 ], 254 nm ultraviolet light (UV) [ 53 , 54 , 60 , 61 ] and chemotherapeutic agents [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

Section: Cancer Cell Response To Genotoxic Stress: Reversible Growmentioning

confidence: 99%

“…For UV, the presence of an apoptotic threshold is observed not only in nucleotide excision repair-proficient (normal) cells, but also in repair-deficient cells derived from patients with the neurodegenerative disorders xeroderma pigmentosum and Cockayne syndrome [ 54 , 63 ] (also see Figure 3 ). In both excision repair-proficient and -deficient cells, loss of colony forming ability following UV exposure is largely (if not totally) associated with SIPS.…”

Section: Cancer Cell Response To Genotoxic Stress: Reversible Growmentioning

confidence: 99%

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The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

Mirzayans

Andrais

Kumar

et al. 2016

IJMS

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It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and triggers growth arrest (e.g., through premature senescence) in some genetic backgrounds; such growth arrested cells remain viable, secrete growth-promoting factors, and give rise to progeny with stem cell-like properties. In addition, caspase 3, which is best known for its role in the execution phase of apoptosis, has been recently reported to facilitate (rather than suppress) DNA damage-induced genomic instability and carcinogenesis. This observation is consistent with an earlier report demonstrating that caspase 3 mediates secretion of the pro-survival factor prostaglandin E2, which in turn promotes enrichment of tumor repopulating cells. In this article, we review these and related discoveries and point out novel cancer therapeutic strategies. One of our objectives is to demonstrate the growing complexity of the DNA damage response beyond the conventional “repair and survive, or die” hypothesis.

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Section: Cancer Cell Response To Genotoxic Stress: Reversible Growsupporting

confidence: 71%

Section: Cancer Cell Response To Genotoxic Stress: Reversible Growmentioning

confidence: 99%

Section: Cancer Cell Response To Genotoxic Stress: Reversible Growmentioning

confidence: 99%

See 1 more Smart Citation

The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

Mirzayans

Andrais

Kumar

et al. 2016

IJMS

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“…Ray and colleagues found that p53 immunoreactivity was predictive of poor outcome in a large group of MB patients 22 . Experimental studies also propose that p53 protects against drug-induced cell death in medulloblastoma cells and play role in chemotherapy resistance 23 . However, in few other studies p53 expression was not statistically associated with patient survival 24 .…”

Section: Discussionmentioning

confidence: 99%

Çocukluk çağı medulloblastom olgularında P53, ERBB2, c-Kit ve BCL2 Ekspresyonunun prognostik ve klinik önemi

Ocak¹,

Özkan²,

Özkan³

et al. 2019

Cukurova Medical Journal

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Öz Purpose: The objective of this study is to evaluate prognostic implications of clinical, histopathological features and immuhistochemical expressions of p53, ERBB2, c-Kit and Bcl-2 in pediatric medulloblastoma. Materials and Methods: A total of 29 pediatric medulloblastoma cases were evaluated for prognostic association of demographic, clinical, histopathological features and immunohistochemical expressions of p53, ERBB2, c-Kit and Bcl-2. Results: Median age at diagnosis was 69 months (21-122 months). Median duration of follow-up was 54 months (2-209 months). Fourteen of samples were diagnosed as classical (48%), thirteen cases as nodular/desmoplastic (45%) and two cases as anaplastic (7%) subtype. Staining for c-Kit, Bcl-2, p53 and ERBB2 was positive in 28, 10, 9 and 2 samples, respectively. Overall (OS) and event-free survival (EFS) were 62 % and 52%, respectively. Bcl-2 expression was found to be significantly increased in nodular/desmoplastic subtype. None of the clinical, histopathological and immunohistochemical features were related to survival. Conclusion: This study reflects the earliest periods of current multimodal treatment protocols of medulloblastoma with similar survival rates in literature. Although none of the proposed factors have been associated with survival, future studies combining molecular and immunohistochemical methods would be more convenient for detecting new prognostic criteria in pediatric medulloblastoma.

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“…13 papers were identified in both of these searches. 11 papers presented evidence of autophagy manipulation on brain tumor models; of which seven presented evidence specific to the pediatric brain tumors rather than adult pathology; with two finding no effect of autophagy modulation on cell survival [ 9 , 81 ]. Abbreviations: chloroquine, CQ; knockout, KO.…”

Section: Relevance To Pediatric Brain Tumorsmentioning

confidence: 99%

Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors

et al. 2018

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Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a “Janus”-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors.

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The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells

Cited by 16 publications

References 55 publications

The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

Çocukluk çağı medulloblastom olgularında P53, ERBB2, c-Kit ve BCL2 Ekspresyonunun prognostik ve klinik önemi

Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors

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