Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy

Huang, Qian; Li, Fangfang; Liu, Xinjian; Li, Wenrong; Shi, Wei; Liu, Feifei; O’Sullivan, Brian; He, Zhiwei; Peng, Yuanlin; Tan, Aik Choon; Zhou, Ling; Shen, Jingping; Han, Gangwen; Wang, Xiao Jing; Thorburn, Jackie; Thorburn, Andrew; Jimeno, Antonio; Raben, David; Bedford, Joel S.; Li, Chuan-Yuan

doi:10.1038/nm.2385

Cited by 721 publications

(744 citation statements)

References 26 publications

(26 reference statements)

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“…159 Indeed, it was observed that caspase-3 is activated in dying tumor cells and causes increased secretion of PGE 2 that results in tumor cell repopulation and resistance to radiotherapy. 160 Further support to this study comes from human trials where two different cohorts of head and neck cancer patients and breast cancer patients, had high expression of active caspase-3 (cleaved caspase-3) and associated increased recurrence of the disease. This suggests that apoptosis is an essential aspect of tumor growth, and paracrine signals released by dying cells act to promote repopulation of these tumor cells and aids further growth.…”

Section: Caspases In Tumorigenesismentioning

confidence: 63%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Section: Caspases In Tumorigenesismentioning

confidence: 63%

Old, new and emerging functions of caspases

et al. 2014

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“…9 A recent study showed that when injected into mice, irradiated mouse embryonic fibroblasts can induce sustained growth of feeder tumour cells. 10 Specifically, this study shows that caspase 3, the executioner of apoptosis, stimulates prostaglandin E2 expression and growth of surviving tumour cells. Other studies also demonstrate that mice deficient for the p53 inhibitor, MDM2, develop intestinal hyperplasia due to the activation of the canonical Wnt and EGFR pathways.…”

mentioning

confidence: 74%

Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation

Dichtel-Danjoy

Dourlen

et al. 2012

Cell Death Differ

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Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (DΔNp53). Historically, DΔNp53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that DΔNp53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and DΔNp53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of DΔNp53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to DΔNp53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that DΔNp53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology

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“…Increased caspase 3 expression is found in OSCC compared with normal oral epithelium 76. These findings question the apoptotic role of caspase 3, suggesting its nonapoptotic functions in oral cancers, as implicated in other cancers 77, 78, 79.…”

Section: Notch Signaling In Head and Neck Squamous Cell Carcinoma (Hnmentioning

confidence: 87%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy

Cited by 721 publications

References 26 publications

Old, new and emerging functions of caspases

Old, new and emerging functions of caspases

Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

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