Sensitization of (colon) cancer cells to death receptor related therapies

Pintzas, Alexander; Zhivotovsky, Boris; Workman, Paul; Clarke, Paul A.; Linardopoulos, Spiros; Martinou, Jean‐Claude; Lacal, Juan Carlos; Robine, Sylvie; Nasioulas, George; Anděra, Ladislav

doi:10.4161/cbt.19600

Cited by 4 publications

(6 citation statements)

References 58 publications

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“…Therefore, different combinations of TRAIL with drugs were proposed to improve the apoptotic response. 14 In this study, using a panel of NSCLC cell lines, we demonstrate that most of these cells quickly and efficiently die upon TRAIL treatment, and apoptotic response in all studied cell lines is dependent on the expression of DR4. Importantly, we found that in comparison to non-neoplastic tissues, lung adenocarcinomas express higher levels of DR4 and caspase-8, suggesting that TRAIL will preferentially kill these tumor cells.…”

mentioning

confidence: 61%

Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling

et al. 2013

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TNF-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for killing tumor cells. However, a number of studies have demonstrated that different cancer cells resist TRAIL treatment and, moreover, TRAIL can promote invasion and metastasis in resistant cells. Here we report that TRAIL rapidly activates caspase-8 in a panel of non-small-cell lung carcinomas (NSCLCs). Adenocarcinomas derived from the lung in addition to high caspase-8 expression are characterized by increased expression of DR4 compared with adjacent non-neoplastic tissues. Blocking DR4 or lowering caspase-8 expression significantly reduced apoptosis in NSCLC cell lines, indicating the importance of DR4 and signifying that higher levels of caspase-8 in lung adenocarcinomas make them more susceptible to TRAIL treatment. Despite rapid and robust initial responsiveness to TRAIL, surviving cells quickly acquired resistance to the additional TRAIL treatment. The expression of cellular-FLIP-short (c-FLIPS) was significantly increased in surviving cells. Such upregulation of c-FLIPS was rapidly reduced and TRAIL sensitivity was restored by treatment with cycloheximide. Silencing of c-FLIPS, but not c-FLIP-long (c-FLIPL), resulted in a remarkable increase in apoptosis and significant reduction of clonogenic survival. Furthermore, chelation of intracellular Ca2+ or inhibition of calmodulin caused a rapid proteasomal degradation of c-FLIPS, a significant increase of the two-step processing of procaspase-8, and reduced clonogenicity in response to TRAIL. Thus, our results revealed that the upregulation of DR4 and caspase-8 expression in NSCLC cells make them more susceptible to TRAIL. However, these cells could survive TRAIL treatment via upregulation of c-FLIPS, and it is suggested that blocking c-FLIPS expression by inhibition of Ca2+/calmodulin signaling significantly overcomes the acquired resistance of NSCLC cells to TRAIL.

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confidence: 61%

Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling

et al. 2013

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“…A remarkable efficacy is appears following the use of a TRAIL with active specific oncogene inhibitor. The combination of inhibitors of selected oncogene such as BRAF or Hsp90 with TRAIL sensitize tumor cells more to death (Pintzas et al, ). Furthermore BRAF inhibitor, PLX4720, and TRAIL cooperate together to overcome oncogenic PIK3CA resistance.…”

Section: Death Receptors and Heterogeneity Of Colorectal Cancermentioning

confidence: 99%

Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer

Marjaneh

Hassanian

Ghobadi

et al. 2018

Journal Cellular Physiology

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Despite advances in the diagnosis and treatment of colorectal cancer (CRC), it remains a major cause of cancer related death globally. There are currently no chemotherapeutic agents that have been found to eradicate the disease without adverse effects. A defect in the death receptor signaling pathway is a feature of CRC. The ligand of these receptors belongs to the tumor necrosis factor family, and that are particularly expressed by cells of the immune system, and that induce apoptosis in a caspase dependent manner. The fact that malignant cells are particularly sensitive to these ligands, compared to normal cells, has led to work on the assessment of compounds that activate this pathway in the treatment of CRC. Phase I trials have shown that these death receptor agonists are safe. Phase II and III trials are currently investigating the efficacy of these therapeutic agents in the treatment of CRC. In this review, we describe the biochemical death receptor signaling pathway and its relationship to CRC. We also summarize the current clinical studies that are targeting this signaling pathway in CRC treatment.

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“…1,7,32 Hence, we reasoned that, being TRAIL the upstream element of the pathway, a correlation between cellular TRAIL levels and the apoptotic susceptibility to rhTRAIL could emerge only when alterations in downstream elements of the extrinsic pathway are not present.…”

Section: Trail Levels Correlates With the Responsiveness To Trailindumentioning

confidence: 99%

“…A combined approach could represent an ideal therapy to elicit apoptosis in resistant cells. 1,7 Histone deacetylase inhibitors, the proteasome inhibitor bortezomib, or compounds that trigger ER-stress can synergize with TRAIL to kill resistant cells. [15][16][17] Bortezomib, for example can sustain TRAIL induced apoptosis through multiple mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6] The resistance to TRAIL induced apoptosis, frequently acquired by cancer cells has limited the therapeutic possibilities of recombinant human TRAIL (rhTRAIL), or agonistic antibodies against its receptors. 1,7 Neoplastic cells adapt different strategies to limit the apoptotic influence of TRAIL including increased expression of: decoy receptors, 8 cFLIP, 9 X-linked inhibitor of apoptosis (XIAP), and of anti-apoptotic Bcl-2 family members. [10][11][12] Also the engagement of different signaling pathways such as the NFκB and the PI3K/Akt can influence the responsiveness to TRAIL.…”

Section: Introductionmentioning

confidence: 99%

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The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels

Manini

Sgorbissa

Potu

et al. 2013

Cancer Biology & Therapy

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Sensitization of (colon) cancer cells to death receptor related therapies

Cited by 4 publications

References 58 publications

Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling

Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca2+/calmodulin signaling

Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer

The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels

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