Loss of Caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis

Brown, Matthew F.; Leibowitz, Brian J.; Chen, D; He, Kan; Zou, Fangdong; Sobol, Robert W.; Beer‐Stolz, Donna; Zhang, Lin; Yu, Jian

doi:10.1038/cddis.2015.104

Cited by 46 publications

(40 citation statements)

References 42 publications

(61 reference statements)

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“…For example, HeLa cervical cancer cells are well known for their resistance to necroptosis, and they express normal levels of RIP1 but no RIP3 expression (66,67). Notably, HCT116 cells have also been reported to lack RIP3 protein (5,68). However, in the present study, HCT116 p53 +/+ cells underwent necroptosis under the stress of serum starvation; therefore, it remains to be determined as to how HCT116 cells undergo necroptosis.…”

Section: Discussionmentioning

confidence: 64%

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

Jung

Quynh

et al. 2018

Int J Oncol

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Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP-activated protein kinase (AMPK) in nutrient/serum starvation-induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53 -/-) compared with in HCT116 cells harboring wild-type p53 (HCT116 p53 +/+ ), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53 -/cells compared with in HCT116 p53 +/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53 +/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53 -/cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53 -/cells compared with in HCT116 p53 +/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53 -/cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53 -/cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53 +/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53 -/cells under serum-depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53 -/cells, but not in HCT116 p53 +/+ cells.

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Section: Discussionmentioning

confidence: 64%

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

Jung

Quynh

et al. 2018

Int J Oncol

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“…These molecules are also central in a complex which assembles independently of death receptor activation, referred to as the ripoptosome (Tenev et al., 2011). It acts cooperatively in different combinations: (1) to control cell fate upon genotoxic stress in concert with NEMO (Biton and Ashkenazi, 2011), (2) together with RIPK3 to control the non-canonical inflammasome activation (Kang et al., 2013), (3) together with RIPK1 to control TNF-α expression NF-κB independently via JNK (Christofferson et al., 2012), and together with caspase-3 to suppress necrosis (Brown et al., 2015). Moreover, (4) a different complex, the PIDDosome (Tinel and Tschopp, 2004), is activated by ATM and executes apoptosis in response to DNA damage (Ando et al., 2012).…”

Section: Discussionmentioning

confidence: 99%

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

et al. 2017

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SummaryConcomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

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“…The antimitotic drug taxol can induce RIP1-dependent necroptosis mediated through FADD double phosphorylation by the mitotic kinases Aurora-A and Plk1 [103]. 5-Fluorouracil (5-FU), etoposide, and camptothecin induced RIP1/MLKL-dependent, but RIP3-independent necroptosis in caspase-3-deficient colorectal cancer cells [104]. Cisplatin caused RIP3-dependent necroptosis in apoptosis-resistant esophageal cancer cells through necrosome formation and autocrine TNF-α signaling [105].…”

Section: Necroptosis In Anti-cancer Therapiesmentioning

confidence: 99%

Necroptosis: an alternative cell death program defending against cancer

Chen

Zhang

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

127

111

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One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells.

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Loss of Caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis

Cited by 46 publications

References 42 publications

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

Necroptosis: an alternative cell death program defending against cancer

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