Role of apoptosis in basal cell and squamous cell carcinoma formation

Erb, Peter C.; Ji, Jingmin; Wernli, Marion; Kump, Erwin; Glaser, Andrea; Büchner, S.

doi:10.1016/j.imlet.2005.06.008

Cited by 63 publications

(62 citation statements)

References 25 publications

(31 reference statements)

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“…Conversely, overexpression of Sphk1 in insensitive KJDSV40 cells resulted in increases in Sphk1 protein level ( Figure 3E), enzyme activity ( Figure 3F), S1P production ( Figure 3G) and reduced sensitivity to doxorubicin compared to vector control ( Figure 3H). S1P is the product of Author Manuscript Published OnlineFirst on November 19, 2014;DOI: 10.1158/1078-0432.CCR-14-1962 apoptotic effects of Sphk1 (27,29). Consistent with this, we found that treatment of KJDSV40 cells with 1 M S1P reduced cytotoxicity by 2.6 fold ( Figure 3I).…”

Section: Sphk1 Inhibition Sensitizes Scc Cells To Doxorubicin-inducedsupporting

confidence: 79%

“…Alternatively, E2F7 could act in a dominant-negative manner by blocking the binding of other E2F repressor complexes. Regardless of the mechanism, our functional data shows that E2F7 regulates S1P levels via induction of Sphk1 19, 2014;DOI: 10.1158/1078-0432.CCR-14-1962 immunity (29). In particular, ceramide and sphingosine have been shown to be profoundly pro-apoptotic whilst phosphorylated sphingosine (S1P) is profoundly anti-apoptotic (27)(28)(29).…”

Section: Discussionmentioning

confidence: 87%

“…Sphk1 is a kinase responsible for the conversion of sphingosine to sphingosine-1-phosphate (S1P) (27)(28)(29) November 19, 2014;DOI: 10.1158/1078-0432.CCR-14-1962 indicates statistically significant increases in Sphk1 expression in breast, colon, lung, ovary, prostate, melanoma, stomach, uterus as well as squamous cell carcinoma and it's precursor actinic keratosis (28). Importantly, Sphk1 has been shown to modulate proliferation, differentiation and apoptosis in KCs (30).…”

Section: Sphingosine Kinase 1 (Sphk1) Is a Downstream Effector Of E2fmentioning

confidence: 99%

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The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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Among keratinocyte-derived squamous cell carcinoma (SCC), cutaneous SCC (CSCC) is the second most common cutaneous cancer type and the most common of the potentially fatal skin cancers. Approximately 90% of head and neck cancers are SCC (HNSCC) and HNSCC worldwide is the sixth most common cancer type afflicting mankind. While resectable disease may be treated by surgery with radiation or chemoradiation, there are still no curative options for advanced, unresectable disease. However, chemotherapy alone may offer a hope for unresectable, disseminated SCC, where 50-60% of patients have disease recurrence within 2 years and approximately 30% of these develop metastatic disease. The mainstay of chemotherapeutic treatment in SCC is the platinum-based drug, cisplatin, 5-fluorouracil (5-FU), taxanes, and anti-EGFR monoclonal antibody such as Cetuximab. Nonetheless, despite advances in treatment techniques, the 5-year survival rate still remains at around 55%.Therefore, there remains a lack of options for recurrent or metastatic disease.The E2F family of transcription factors has emerged as key regulators of proliferation, differentiation and response to stress and apoptotic stimuli in keratinocytes. Consistent with these roles, dysregulation of E2F expression/activity is a common occurrence in cancer and SCC in particular. Thus, better understanding of the E2F family of proteins is essential to establish how these processes are disrupted during SCC genesis. The E2F network exists as a complex map of interacting pathways, and the complete understanding of the E2F family will not be possible until physiological functions of newly identified inhibitory E2F proteins, E2F7 and E2F8, are fully revealed. I provide strong evidence, from in vitro experiments, that E2F7 plays a unique and non-redundant role in modulating UV-or chemotherapy-induced cytotoxicity whereas E2F8 has a unique and non-redundant capacity to regulate squamous differentiation. In addition, I report on a unique feedback loop between E2F1, E2F7 and E2F8 that highlights a previously unreported interdependent axis.With respect to E2F7-specific functions, my work characterised two previously unidentified pathways as therapeutic targets, E2F7/Sphk1/S1P/AKT and E2F7/RacGAP1/AKT, by which the transcription factor E2F7 suppresses doxorubicin specific sensitivity in SCC cells.Targeting these pathways has the potential to expand the clinical activity of existing chemotherapeutics. I provide, in vitro, in vivo and patient data in this study that shows that E2F7-dependent repression of doxorubicin sensitivity is mediated via the induction of Sphingosine kinase 1 (Sphk1) and Rac GTPase activating protein 1 (RacGAP1). These are iii both novel findings and have significant implications for drug resistant SCC. Specifically, Ishowed that (i) E2F7 is overexpressed in patient SCCs and inhibits sensitivity to doxorubicin, (ii) that E2F7-dependent doxorubicin resistance is mediated via E2F-dependent induction of Sphk1 leading to overproduction of Sphingosine-1-phosphate ...

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Section: Sphk1 Inhibition Sensitizes Scc Cells To Doxorubicin-inducedsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 87%

Section: Sphingosine Kinase 1 (Sphk1) Is a Downstream Effector Of E2fmentioning

confidence: 99%

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The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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“…Furthermore, removal of CPDs from ssUVR-irradiated human skin through the application of SS plus photolyase resulted in a relatively high level of protection against ssUVR-induced apoptotic cell death in human skin. In general, UVR not only induces DNA damage in epidermal cells, but it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and -preventing molecules (24). If the DNA damage is not repaired or the damaged cells are not eliminated by apoptosis, this can lead to cell transformation, uncontrolled proliferation and eventually skin tumor formation (24).…”

Section: Discussionmentioning

confidence: 99%

“…In general, UVR not only induces DNA damage in epidermal cells, but it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and -preventing molecules (24). If the DNA damage is not repaired or the damaged cells are not eliminated by apoptosis, this can lead to cell transformation, uncontrolled proliferation and eventually skin tumor formation (24). In this context, apoptosis provides an efficient safeguard mechanism against cancer (25,26).…”

Section: Discussionmentioning

confidence: 99%

Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: Clues to skin cancer prevention

et al. 2011

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Abstract. The exposure of human skin to ultraviolet radiation (UVR) results in the formation of DNA photolesions that give rise to photoaging, mutations, cell death and the onset of carcinogenic events. Photolyase (EC 4.1.99.3) is a DNA repair enzyme that reverses damage caused by exposure to UVR. We sought to investigate whether addition of photolyase enhances the protection provided by a traditional sunscreen (SS), by reducing the in vivo formation of cyclobutane-type pyrimidine dimers (CPDs) and UVR-induced apoptosis in human skin. Ten volunteers (Fitzpatrick skin type II) were exposed to solar-simulated (ss) UVR at a three times minimal erythema dose for 4 consecutive days. Thirty minutes prior to each exposure, the test materials [vehicle, SS (sun protection factor 50) alone, and SS plus photolyase from Anacystis nidulans] were applied topically to three different sites. One additional site was left untreated and one received ssUVR only. Biopsy specimens were taken 72 h after the last irradiation. The amount of CPDs and the extent of apoptosis were measured by ELISA. Photolyase plus SS was superior to SS alone in reducing both the formation of CPDs and apoptotic cell death (both P<0.001). In conclusion, the addition of photolyase to a traditional SS contributes significantly to the prevention of UVR-induced DNA damage and apoptosis when applied topically to human skin.

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Usnic acid alleviates inflammatory responses and induces apoptotic signaling through inhibiting NF‐ĸB expressions in human oral carcinoma cells

Azhamuthu,

Kathiresan,

Senkuttuvan

et al. 2024

Cell Biochemistry & Function

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Usnic acid (UA) is a unique bioactive substance in lichen with potential anticancer properties. Recently, we have reported that UA can reduce 7,12‐dimethylbenz[a] anthracene‐induced oral carcinogenesis by inhibiting oxidative stress, inflammation, and cell proliferation in a male golden Syrian hamster in vivo model. The present study aims to explore the relevant mechanism of cell death induced by UA on human oral carcinoma (KB) cell line in an in vitro model. We found that UA can induce apoptosis (cell death) in KB cells by decreasing cell viability, increasing the production of reactive oxygen species (ROS), depolarizing mitochondrial membrane potential (MMP) levels, causing nuclear fragmentation, altering apoptotic morphology, and causing excessive DNA damage. Additionally, UA inhibits the expression of Bcl‐2, a protein that promotes cell survival, while increasing the expression of p53, Bax, Cytochrome‐c, Caspase‐9, and 3 proteins in KB cells. UA also inhibits the expression of nuclear factor‐κB (NF‐κB), a protein that mediates the activation of pro‐inflammatory cytokines such as TNF‐α and IL‐6, in KB cells. Furthermore, UA promotes apoptosis by enhancing the mitochondrial‐mediated apoptotic mechanism through oxidative stress, depletion of cellular antioxidants, and an inflammatory response. Ultimately, the findings of this study suggest that UA may have potential as an anticancer therapeutic agent for oral cancer treatments.

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Role of apoptosis in basal cell and squamous cell carcinoma formation

Cited by 63 publications

References 25 publications

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: Clues to skin cancer prevention

Usnic acid alleviates inflammatory responses and induces apoptotic signaling through inhibiting NF‐ĸB expressions in human oral carcinoma cells

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