Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric caner

Zhai, Ertao; Chen, Jianhui; Wang, Kang; Ye, Zhijun; Wang, Hui; Chen, Chuangqi; Changjiang, Qin; Chen, Sile; He, Yulong; Cai, Shirong

doi:10.1007/s13277-016-5229-1

Cited by 62 publications

(41 citation statements)

References 25 publications

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“…In this point, we propose that patients who have a relatively low level of MLKL in tumor tissues are more likely to respond to TRAIL receptor agonists due to the perturbation in endosomal trafficking of the TRAIL receptor agonist. Abnormal expression of MLKL has been detected in many kinds of tumors, such as colon cancer, ovarian cancer, and gastric cancer [34][35][36] and recent studies also have revealed that MLKL could serve as a potential prognostic biomarker for patients with cancer [37][38][39] . In these studies, the authors revealed that decreased expression of MLKL was significantly associated with poor overall survival in cancer patients suggesting a prognostic and clinicopathological significance of expression level of MLKL in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Park

et al. 2020

Cell Death Dis

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Mixed lineage kinase domain-like (MLKL) is an essential molecule of necroptosis, a cell death process that is initiated by direct disruption of the plasma membrane. During necroptosis, MLKL is phosphorylated by receptor interacting protein kinase-3 (RIPK3 or RIP3), and then translocates to the plasma membrane to disrupt membrane integrity. Recent data suggest that MLKL also has a RIP3-indendent function in the generation of intraluminal and extracellular vesicles (EVs), as well as in myelin sheath breakdown when promoting sciatic nerve regeneration. Here we show that depletion of MLKL enhances TRAIL-induced cell death in a RIP3-independent manner. Depletion of MLKL leads to prolonged cytotoxic signals that increase TRAIL-induced cell death. Initially, TRAIL binds to DR5 at the cell surface and is endocytosed at similar rates in MLKL-expressing and MLKL-depleted cells, eventual degradation of intracellular TRAIL by the lysosome is delayed in MLKL-depleted cells, corresponding with prolonged/enhanced intracellular signals such as p-ERK and p-p38 in these cells. Colocalization of TRAIL with the marker of early endosomes, EEA1 suggests that TRAIL is accumulated in early endosomes in MLKL-depleted cells compared to MLKL-expressing cells. This indicates that depletion of MLKL reduces receptor-ligand endosomal trafficking leading to increased TRAIL-cytotoxicity. An MLKL mutant that compromises its necroptotic function and its function in the generation of EVs was sufficient to rescue MLKL deficiency, suggesting that the N-terminal structural elements necessary for these functions are not required for the function of MLKL in the intracellular trafficking associated with regulating death receptor cytotoxicity. A reduction in MLKL expression in cancer cells would therefore be expected to result in enhanced TRAIL-induced therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Park

et al. 2020

Cell Death Dis

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“…A reduced expression of key molecules in the necroptotic pathway has been observed in different cancer cell lines, suggesting that these cells may evade necroptosis to survive [6]. As a consequence, a lower expression of necroptosis regulators seems to correlate with a worse prognosis in several types of carcinomas (i.e., breast, colorectal, gastric, and ovarian cancer, and head and neck and cervical squamous cell carcinoma), in acute myeloid leukemia, and in melanoma [30,[42][43][44][45][46][47][48]. However, the expression of RIPK1, RIPK3, and MLKL has been found to be upregulated in some cancers (i.e., glioblastoma, pancreatic, lung, and esophageal cancer), in which a high activation of the necroptotic cascade seems to be correlated with a poorer prognosis in different studies [6,36,41,[49][50][51][52][53].…”

Section: Pro-tumoral Effects Anti-tumoral Effectsmentioning

confidence: 99%

Necroptosis in Cholangiocarcinoma

Sarcognato

Jong

Fabris

et al. 2020

Cells

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Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.Cells 2020, 9, 982 2 of 18 (RIPK3) and mixed lineage kinase domain-like (MLKL) [4]. Therefore, necroptosis is an alternative mode of CD when the caspase-8-dependent apoptotic pathway is blocked. It is now well-established that various stimuli can initiate necroptosis, including intra-and extracellular factors, such as tumor necrosis factor α (TNFα) and reactive oxygen species (ROS) [5].A hallmark of cancer is the ability of malignant cells to evade apoptosis. Therefore, the induction of necroptosis could be an alternative strategy for killing cancer cells. Several therapeutics able to affect the necroptotic cascade have recently been developed, and a few of them are already in phase 1 trials for the treatment of inflammatory diseases. Moreover, necroptosis modulation is becoming the target of several new anti-cancer strategies. In fact, it has been demonstrated that apoptosis-resistant tumors respond to necroptosis, and that necroptosis can create an immunogenic microenvironment that enhances tumor clearance [6]. These aspects will be further discussed in the following chapters.Herein, we will discuss the general aspects of necroptosis and what is currently known on its involvement in cholangiocarcinoma (CCA), in order to provide perspectives for future studies in this relatively new field. Overview on Types of Cell DeathIn 2005, the Nomenclature Committee on Cell Death (NCCD) defined the first CD classification purely based on morphological criteria. This classification included three major forms of CD: types I, II, and III [7]. Type I CD, termed apoptosis, exhibits cell shrinkage, membrane blebbing, DNA fragmentation, chromatin condensation, and the formation of apoptotic bodies. Apoptosis is a form of RCD and responds to two different death signals: damage from inside the cell, such as DNA damage, which elicits an intrinsic pathway, and extracellular stimuli, such as TNFα and the Fas ligand, ...

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“…It is phosphorylated by RIPK3 to form an oligomeric structure that translocates to the plasma membrane to disrupt membrane integrity and this can be used as a biochemical signature for necroptosis [19]. Studies have demonstrated that low MLKL expression indicated poor prognosis in colon cancer [20], ovarian cancer [21], and gastric cancer [22], indicating that MLKL might serve as a candidate tumor suppressor and a potential prognostic biomarker for various types of cancers. However, the majority of their experimental results were obtained from the tissue samples.…”

Section: Discussionmentioning

confidence: 99%

Low Necroptosis Process Predicts Poor Treatment Outcome of Human Papillomavirus Positive Cervical Cancers by Decreasing Tumor-Associated Macrophages M1 Polarization

Lin

Song

Zang³

2018

Gynecol Obstet Invest

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Background/Aim: The aim of this study was to assess the functions of the necroptosis process on the prognosis of high-risk human papillomavirus (HR-HPV)-related cervical cancer. Methods: PCR and western blotting were used to demonstrate the expression of the necroptosis marker, mixed lineage kinase domain-like protein (MLKL), in whole blood and peripheral blood mononuclears (PBMCs) of 89 cervical cancer patients and 15 healthy volunteers. Necroptosis levels and M1 polarization were determined in tumor co-cultured macrophages. Results: We found that MLKL expressions were significantly increased in cervical cancer patients in both whole blood and PBMC samples compared to the expressions in the healthy controls. Low MLKL expression was significantly associated with decreased survival rate in overall survival and disease-free survival. Co-culture cervical cancer cells decrease the necroptosis process of macrophage, together with the proinflammatory factors (M1 markers) downregulation, and this negative regulation was exacerbated in HPV-positive cases. Necroptosis enhancer RIPK3 overexpression showed reversed regulation of these M1 markers, suggesting that co-culture cervical cancer cells decrease the macrophage M1 polarization partly through necroptosis downregulation. Conclusion: Our study revealed that necroptosis process could be a relevant marker for the determination of the prognosis in cervical cancer patients, which might be because of its role in regulating macrophage polarization.

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Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric caner

Cited by 62 publications

References 25 publications

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Necroptosis in Cholangiocarcinoma

Low Necroptosis Process Predicts Poor Treatment Outcome of Human Papillomavirus Positive Cervical Cancers by Decreasing Tumor-Associated Macrophages M1 Polarization

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