cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition

Padmanabhan, Chandrasekhar; Rellinger, Eric J.; Zhu, Jing; An, Hanbing; Woodbury, Luke; Chung, Dai H.; Waterson, Alex G.; Lindsley, Craig W.; Means, Anna L.; Beauchamp, R. Daniel

doi:10.18632/oncotarget.19557

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Our findings support these observations, as ML327 induces epithelial-like features and sensitizes ES cells to TRAIL-mediated apoptosis. We have previously reported the capacity of ML327 to mediate TRAIL sensitization in colon cancer cells, demonstrating this process to be in part mediated by down regulation of cFLIPs [18]. Our results are in support of our previous investigation, as we observe consistent downregulation of cFLIPs in association with ML327-mediated TRAIL sensitization.…”

Section: Discussionsupporting

confidence: 92%

“…ML327 has previously been shown to reduce cFLIPs expression in colon cancer cell lines, thereby sensitizing them to TRAIL-induced apoptosis [18]. We therefore analyzed the response of cFLIPs to ML327 treatment in 3 ES cell lines and found that cFLIPs protein was reduced (Figs.…”

Section: Resultsmentioning

confidence: 97%

“…We have systemically expanded our observations to encompass tumors of neural crest origin, neuroblastoma, and now cells of mesenchymal origin (ES) [11]. E-cadherin is consistently upregulated by ML327 in all tested cell lines (colon, lung, breast, neuroblastoma, and ES cells) with the exception of RKO (colon) and MDA-MB-231 (breast) cancer cells, whose E-cadherin promoters are silenced by DNA hypermethylation [10,18]. Intriguingly, the predominant cellular response observed within colon and lung carcinomas is blockade of cellular migration with no observed changes in cellular viability appreciated in vitro and in vivo [10].…”

Section: Discussionmentioning

confidence: 99%

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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Rellinger

Padmanabhan²,

Qiao

et al. 2017

Biochemical and Biophysical Research Communications

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Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Rellinger

Padmanabhan²,

Qiao

et al. 2017

Biochemical and Biophysical Research Communications

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“…In TRAIL-sensitive and RPM-EP melanoma cells expressing DR5, TRAIL-mediated apoptosis inhibition was observed; due to the expression of cFLIP, TRAIL-R1 negative melanoma cells could not undergo apoptosis induced by TRAIL [ 44 ] . A study on epithelial-mesenchymal transition (EMT) showed that high expression of cFLIPs in the exogenous region caused resistance to apoptosis triggered by TRAIL, and deletion of cFLIPs was sufficient to overcome TRAIL resistance in carcinoma cell lines; when ML327 (an isoxazole-based small chemical) was induced into an immortalized mouse mammary epithelial cell line, there was a partial reversal of TGF-β-induced EMT [ 45 ] .…”

Section: Trail and Cancer Therapymentioning

confidence: 99%

Nano-TRAIL: a promising path to cancer therapy

Gampa¹

2023

Cancer Drug Resist

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Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL’s potential as an anticancer agent.

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“…Because EMT leads to the dysregulation and disassembly of this E-cadherin–TRAIL complex, cancer cells with a mesenchymal phenotype increase their protection against TRAIL-induced apoptosis. 81 However, in patients with early-detected colorectal cancer, DR4 and DR5 can be expressed in parallel with E-cadherin, but their co-localisation at the membrane is not systematic. 82 Moreover, the potential interactions between the death receptors (including the decoy receptors known as death receptor competitors that lack the intracellular death domain responsible for the propagation of TRAIL-induced apoptotic signal) and cadherins remains unanswered, despite the potential mechanistic impact these cell processes hold.…”

Section: Death Receptor-mediated Features Of Emtmentioning

confidence: 99%

TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms

et al. 2020

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The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the ability to escape cell death upon cytotoxic treatments. EMT has recently been suggested to drive a heterogeneous cellular environment that appears favourable for tumour progression. Recent studies have highlighted a link between EMT and cell sensitivity to TRAIL, whereas others have highlighted their effects on the induction of EMT. This review aims to explore the molecular mechanisms by which death signals can elicit an increase in response heterogeneity in the metastasis context, and to evaluate the impact of these processes on cell responses to cancer therapeutics.

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cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition

Abstract: ABSTRACT

Cited by 7 publications

References 53 publications

ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Nano-TRAIL: a promising path to cancer therapy

TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms

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