The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy

Cheng, Jin; He, Sijia; Wang, Min; Zhang, Zhengxiang; Xiao, Feng; Ye, Yu; Ma, Jingjing; Dai, Chenyun; Zhang, Shengping; Sun, Lianhui; Gong, Yanping; Wang, Yiwei; Zhao, Minghui; Luo, Yu; Liu, Xinjian; Tian, Ling; Li, Chuan-Yuan; Huang, Qian

doi:10.1158/1078-0432.ccr-18-3001

Cited by 39 publications

(27 citation statements)

References 50 publications

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“…There are other possible pro-oncogenic roles of PC-3/ caspase-3 activity, including promoting a tumorigenic proliferative state, as has been extensively discussed. 18–20,22,23,148…”

Section: Cancer Apoptosis and Procaspase-3mentioning

confidence: 99%

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

2019

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Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.

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“…There are other possible pro-oncogenic roles of PC-3/ caspase-3 activity, including promoting a tumorigenic proliferative state, as has been extensively discussed. 18–20,22,23,148…”

Section: Cancer Apoptosis and Procaspase-3mentioning

confidence: 99%

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

2019

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“…Although our study focuses on the Cox-2/PGE 2 as the downstream effector of caspase-3, radiation-induced dying NSCLC cells may also secrete a cocktail of additional growth-stimulating factors, such as VEGF-A, to contribute to tumor relapse after clinical treatment [12,45]. Also, except for p53/Cox-2 axis, caspase-3 may modulate Cox-2 expression through other pathways.…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Zhao¹,

Wang²,

Zhao³

et al. 2020

Preprint

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Background: Radiotherapy is an effective treatment on non-small-cell lung cancer (NSCLC). However, radiation-induced dying tumor cells are postulated to generate potent growth signals to stimulate the repopulation of adjacent surviving tumor cells, which may promote tumor recurrence. We investigated the role of caspase-3-centered molecular mechanism in NSCLC repopulation after radiotherapy.Methods: The stable caspase-3 knockout (Casp3 KO) NSCLC cells were compared with wild-type cells for growth-promoting effect after radiotherapy using in vitro repopulation model. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay and luciferase reporter assay were used to identify the possible molecules and pathway. To elucidate the function of caspase-3 in tumor repopulation, a series of in vitro assays were performed with Casp3 KO NSCLC cells. Finally, tumor cell growth rate of Casp3 KO and wild-type tumor cells in vivo was tested using xenograft tumor assay and key proteins were further confirmed in tumor tissues with or without radiotherapy.Results: We found that radiation induced DNA damage response (DDR) and caspase-3 activation, as well as promoted tumor repopulation in NSCLC cells. Unexpectedly, depleting caspase-3 significantly attenuated ataxia-telangiectasia mutated kinase (ATM)/p53-mediated DDR via attenuating endonuclease G (EndoG) nuclear migration, thus decreasing the growth-promoting effect of irradiated dying cells. Moreover, we identified p53 as a regulator of the Cox-2/PGE2 axis, which was probably involved in caspase-3-centered tumor repopulation after radiotherapy. Additionally, depleting caspase-3 in NSCLC cells showed impaired tumor growth in nude mice model.Conclusions: Our findings demonstrated that caspase-3 was implicated in tumor repopulation and that was accompanied by promoting DDR and downstream Cox-2/PGE2 axis activation in NSCLC cells. This hitherto undescribed signaling pathway mediated by caspase-3 may deepen insight into the radiobiology and provide therapeutic targets to reduce NSCLC recurrence after radiotherapy.

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“…Therefore, it is possible that pro-apoptotic proteins, mostly caspase 3 confer a pro-survival and pro-invasive phenotype to FIS-treated K562 cells through the PR pathway. However, the assessment of other key molecular players of the PR pathway [e.g., caspase-7, prostaglandin E2 (PGE2), protein kinase Cδ (PKCδ), calcium-independent phospholipase A2 (iPLA2), COX-2, NF-κB] should be performed, among other assays (71-72), to confirm this assumption.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular alterations induced by low‑dose fisetin in human chronic myeloid leukemia cells

Klimaszewska‐Wiśniewska

Grzanka

Czajkowska

et al. 2019

Int J Oncol

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The present study aimed to evaluate the cellular and molecular effects of low concentrations of the flavonoid, fisetin, on K562 human chronic myeloid leukemia cells, in the context of both potential anti-proliferative and anti-metastatic effects. Thiazolyl blue tetrazolium bromide assay, Trypan blue exclusion assay, Annexin V/propidium iodide test, cell cycle analysis, Transwell migration and invasion assays, the fluorescence staining of β-catenin and F-actin as well as reverse transcription-quantitative polymerase chain reaction were performed to achieve the research goal. Furthermore, the nature of the interaction between fisetin and arsenic trioxide in the K562 cells was analyzed according to the Chou-Talalay median-effect method. We found that low concentrations of fisetin had not only a negligible effect on the viability and apoptosis of the K562 cells, but also modulated the mRNA levels of selected metastatic-related markers, accompanied by an increase in the migratory and invasive properties of these cancer cells. Although some markers of cell death were significantly elevated in response to fisetin treatment, these were counterbalanced through anti-apoptotic and pro-survival signals. With decreasing concentrations of fisetin and arsenic trioxide, the antagonistic interactions between the 2 agents increased. On the whole, the findings of this study suggest that careful consideration should be taken when advising cancer patients to take fisetin as a dietary supplement and when considering fisetin as a potential candidate for the treatment of chronic myeloid leukemia. Further more detailed studies are required to confirm our findings.

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The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy

Cited by 39 publications

References 50 publications

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Cellular and molecular alterations induced by low‑dose fisetin in human chronic myeloid leukemia cells

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