Ionizing radiation, but not ultraviolet radiation, induces mitotic catastrophe in mouse epidermal keratinocytes with aberrant cell cycle checkpoints

Wang, Ming; Gao, Qingxiang; Xu, Teng; Pan, MeiPing; Lin, TianMiao; Zhou, Guixuan; Xu, Benhua; Yue, Zhicao

doi:10.1111/exd.13665

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…Data from the Zhicao Yue group has shown that various stresses, such as ultraviolet and ionizing irradiation, are common genotoxic stresses, which may consequently induce cell cycle arrest and skin damage. 37 These stresses were found to modulate the expression of some key transcription factors including ΔNp63α. Westfall et al 38 found that ultraviolet C (UVC) irradiation induces phosphorylation and ubiquitin-mediated degradation of ΔNp63α in NHKs.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet B irradiation up‐regulates MM1 and induces photoageing of the epidermis

Zheng

Chen

Jin

et al. 2021

Photoderm Photoimm Photomed

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Background: ΔNp63α and c-Myc are key transcription factors controlling proliferation and senescence in epithelial cells. We previously reported that the c-Myc modulator MM1 and its E3 ligase, HERC3, together with the transcription factor ΔNp63α, compose a feedback loop, which regulates proliferative senescence in MCF-10A mammary epithelial cells. However, it is unknown whether this loop is involved in skin ageing. On the other hand, ultraviolet B (UVB) rays are assumed to be the main culprits for photoageing of the epidermis, but the underlying mechanisms are obscure.Aims: To investigate whether MM1/ΔNp63α axis is involved in UVB-induced photoageing of the epidermis. Materials and Methods:HaCaT human immortalized keratinocytes overexpressed with MM1, knocked down with c-Myc or irradiated with UVB, were subjected to MTT assays to measure cell proliferation, as well as RT-qPCR or immunoblot to detect the members of MM1/ΔNp63α loop and the cellular senescence markers. Meanwhile, primary normal human keratinocytes (NHKs) or mice were irradiated with UVB, followed by immunoblot analysis, SAβ-gal, haematoxylin-eosin or immunohistochemistry staining. Results: Overexpression of MM1 down-regulated ΔNp63α and induced proliferative senescence in the HaCaT cells. In the HaCaT cells, NHKs and the mouse epidermis, UVB irradiation increased MM1 mRNA level and led to a down-regulation of ΔNp63α, HERC3 and c-Myc, concomitant with cellular senescence or photoageing. Additionally, knock-down of c-Myc induced proliferative senescence in the HaCaT cells and abrogated UVB-induced cellular senescence. Conclusions: UVB up-regulates MM1 and consequently modulates ΔNp63α and c-Myc, which may account for the proliferative senescence of keratinocytes and photoageing of the epidermis.

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Section: Discussionmentioning

confidence: 99%

Ultraviolet B irradiation up‐regulates MM1 and induces photoageing of the epidermis

Zheng

Chen

Jin

et al. 2021

Photoderm Photoimm Photomed

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“…With induced DNA damage from DOX and intercalation and inhibition of thymidylate synthase, cellular checkpoints are activated to arrest cell progression to the replication phase [90,91]. However, cell death during mitosis is activated by caspase-2 and prevents defective or damaged DNA from being replicated and passed on to the daughter cells [92][93][94][95]. Alternatively, checkpoint 1 (Chk1) activation occurs mostly during the S or G2 phases, and recruits repair mechanism pathways, and prevents progression to the M phase [91].…”

Section: Discussionmentioning

confidence: 99%

Sterically Stabilised Polymeric Mesoporous Silica Nanoparticles Improve Doxorubicin Efficiency: Tailored Cancer Therapy

Moodley

Singh

2020

Molecules

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The fruition, commercialisation and clinical application combining nano-engineering, nanomedicine and material science for utilisation in drug delivery is becoming a reality. The successful integration of nanomaterial in nanotherapeutics requires their critical development to ensure physiological and biological compatibility. Mesoporous silica nanoparticles (MSNs) are attractive nanocarriers due to their biodegradable, biocompatible, and relative malleable porous frameworks that can be functionalized for enhanced targeting and delivery in a variety of disease models. The optimal formulation of an MSN with polyethylene glycol (2% and 5%) and chitosan was undertaken, to produce sterically stabilized, hydrophilic MSNs, capable of efficient loading and delivery of the hydrophobic anti-neoplastic drug, doxorubicin (DOX). The pH-sensitive release kinetics of DOX, together with the anticancer, apoptosis and cell-cycle activities of DOX-loaded MSNs in selected cancer cell lines were evaluated. MSNs of 36-60 nm in size, with a pore diameter of 9.8 nm, and a cumulative surface area of 710.36 m 2 /g were produced. The 2% pegylated MSN formulation (PCMSN) had the highest DOX loading capacity (0.98 mg dox /mg msn ), and a sustained release profile over 72 h. Pegylated-drug nanoconjugates were effective at a concentration range between 20-50 µg/mL, inducing apoptosis in cancer cells, and affirming their potential as effective drug delivery vehicles.Molecules 2020, 25, 742 2 of 22 MSNs possess a large active surface area which can be selectively polymerised or functionalised for stimuli-responsive purposes [11], tunable pore size and large pore volumes for the loading and controlled release of the cargo, and have shown favourable tolerance levels both in vitro and in vivo [12][13][14].MSNs are being extensively researched as theranostic devices for diseases, especially for cancer therapy [15]. Conventional cancer treatment options such as surgery, radiotherapy and chemotherapy [16], have not been fully effective, resulting in snowballing recurrence rates and depression in the quality of life [17,18]. Unpleasant side-effects are often linked to the anti-neoplastic drugs used, which act by inhibiting cellular mechanisms of DNA replication that are up-regulated in cancer cells. These cytostatic or cytotoxic compounds usually have low bioavailability and are thus administered at high dosages or for prolonged dosing intervals, leading to systemic side effects at non-specific sites [19,20].Doxorubicin (DOX) remains one of the most efficient anthracycline drugs available and is used in the treatment of diverse cancers, including breast, cervical, bone, gastric and leukaemia [21][22][23]. Despite its popularity, its low solubility [24][25][26], coupled with increased dosing frequencies [27][28][29] has resulted in many associated side effects, including cardiotoxicity [30][31][32], myelosuppression [33,34], induced vomiting with nausea [35,36], and alopecia [18,37]. Critical evaluation of these detrimental side-effects that become more...

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“…In rodent epidermis, this disruption of cell adhesion is mediated by ROS‐activated Src/Abl kinases and subsequent degradation of the E‐cadherin/β‐catenin complex; activation of Wnt and Hippo signalling are then followed to drive skin regeneration . Interestingly, the epidermal keratinocytes do not undergo apoptosis even after 40 Gy IR irradiation; rather, they enter a mitotic catastrophe programme and are replaced by clonal expansion from residual epidermal stem cells …”

Section: Diverse Mechanisms Of How Ionizing Radiation Damages the Normentioning

confidence: 99%

“…IR may induce cell apoptosis, depending on the expression level of IAP proteins and the activation status of EGFR signalling. Mitotic catastrophe is another possible outcome after IR stress, particularly in epidermal keratinocytes…”

Section: Diverse Mechanisms Of How Ionizing Radiation Damages the Normentioning

confidence: 99%

“…For instance in mouse skin, the hair follicles show extensive apoptosis after 5 Gy irradiation, whereas the epidermis is only damaged after 40 Gy irradiation . The fate choices of irradiated cells are complex: cells may resist or undergo apoptosis, senescence, differentiation or mitotic catastrophe, depending on rules that are not fully understood (Figure ) . It is therefore of critical importance to decipher the regulatory mechanisms underlying these diversified cell fate choices in radiation biology.…”

Section: Diverse Mechanisms Of How Ionizing Radiation Damages the Normentioning

confidence: 99%

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How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models

Gao

Zhou

Lin

et al. 2018

Experimental Dermatology

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Chemotherapy and radiotherapy are common modalities for cancer treatment. While targeting rapidly growing cancer cells, they also damage normal tissues and cause adverse effects. From the initial insult such as DNA double‐strand break, production of reactive oxygen species (ROS) and a general stress response, there are complex regulatory mechanisms that control the actual tissue damage process. Besides apoptosis, a range of outcomes for the damaged cells are possible including cell cycle arrest, senescence, mitotic catastrophe, and inflammatory responses and fibrosis at the tissue level. Feather and hair are among the most actively proliferating (mini‐)organs and are highly susceptible to both chemotherapy and radiotherapy damage, thus provide excellent, experimentally tractable model systems for dissecting how normal tissues respond to such injuries. Taking a comparative biology approach to investigate this has turned out to be particularly productive. Started in chicken feather and then extended to murine hair follicles, it was revealed that in addition to p53‐mediated apoptosis, several other previously overlooked mechanisms are involved. Specifically, Shh, Wnt, mTOR, cytokine signalling and ROS‐mediated degradation of adherens junctions have been implicated in the damage and/or reparative regeneration process. Moreover, we show here that inflammatory responses, which can be prominent upon histological examination of chemo‐ or radiotherapy‐damaged hair follicle, may not be essential for the hair loss phenotype. These studies point to fundamental, evolutionarily conserved mechanisms in controlling tissue responses in vivo, and suggest novel strategies for the prevention and management of adverse effects that arise from chemo‐ or radiotherapy.

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Ionizing radiation, but not ultraviolet radiation, induces mitotic catastrophe in mouse epidermal keratinocytes with aberrant cell cycle checkpoints

Cited by 5 publications

References 33 publications

Ultraviolet B irradiation up‐regulates MM1 and induces photoageing of the epidermis

Ultraviolet B irradiation up‐regulates MM1 and induces photoageing of the epidermis

Sterically Stabilised Polymeric Mesoporous Silica Nanoparticles Improve Doxorubicin Efficiency: Tailored Cancer Therapy

How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models

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