ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

Kho, Dhonghyo; Xu, Jing; Gajan, Ambikai; Wu, Zeyu; Wu, Gen Sheng

doi:10.18632/oncotarget.15451

Cited by 32 publications

(29 citation statements)

References 51 publications

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“…All the breast and endometrial cancer cell lines tested were sensitive to ONC201-mediated toxicity with IC50s ranging from 0.78 to 14 μM. These are similar to the IC50s for colon, hematological, and breast cancer cells that have been previously reported [ 8 , 13 , 21 , 49 ]. Cell lines representing all subtypes of breast cancer (ER+, HER2+, and TNBC) and serous and endometrioid endometrial cancer were sensitive to ONC201-mediated growth inhibition ( Supplementary Table 1 ).…”

Section: Discussionsupporting

confidence: 81%

ONC201 kills breast cancer cellsin vitroby targeting mitochondria

Porat-Shliom²,

et al. 2018

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We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.

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Section: Discussionsupporting

confidence: 81%

ONC201 kills breast cancer cellsin vitroby targeting mitochondria

Porat-Shliom²,

et al. 2018

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“…9). This may at least in part explain why IRE1 is found to be required for ER stress-induced cell death in some cell types [49,53,54] while having no effect on cell death in others [18,[92][93][94]. We could not observe any pro-survival effect of IRE1 or XBP1 during Tg-induced cell death in the cell lines we examined.…”

Section: Discussionmentioning

confidence: 68%

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

et al. 2020

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Background: Cell death triggered by unmitigated endoplasmic reticulum (ER) stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin (Tg) is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy. Tg induces apoptosis via the unfolded protein response (UPR), but how apoptosis is initiated, and how individual effects of the various UPR components are integrated, is unclear. Furthermore, the role of autophagy and autophagy-related (ATG) proteins remains elusive.Methods: To systematically address these key questions, we analyzed the effects of Tg and therapeutically relevant Tg analogs in two human cancer cell lines of different origin (LNCaP prostate-and HCT116 colon cancer cells), using RNAi and inhibitory drugs to target death receptors, UPR components and ATG proteins, in combination with measurements of cell death by fluorescence imaging and propidium iodide staining, as well as real-time RT-PCR and western blotting to monitor caspase activity, expression of ATG proteins, UPR components, and downstream ER stress signaling.Results: In both cell lines, Tg-induced cell death depended on death receptor 5 and caspase-8. Optimal cytotoxicity involved a non-autophagic function of MAP1LC3B upstream of procaspase-8 cleavage. PERK, ATF4 and CHOP were required for Tg-induced cell death, but surprisingly acted in parallel rather than as a linear pathway; ATF4 and CHOP were independently required for Tg-mediated upregulation of death receptor 5 and MAP1LC3B proteins, whereas PERK acted via other pathways. Interestingly, IRE1 contributed to Tg-induced cell death in a cell typespecific manner. This was linked to an XBP1-dependent activation of c-Jun N-terminal kinase, which was proapoptotic in LNCaP but not HCT116 cells. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Conclusions: Together, our results provide a new, integrated understanding of UPR signaling mechanisms and downstream mediators that induce cell death upon Tg-triggered, unmitigated ER stress.

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“…Studies have shown that the efficacy of ONC201 in breast cancer, especially TNBC, can involve a number of mechanisms. As seen in other tumor types, TRAIL-dependent induction of cell death by Akt/ERK inhibition and subsequent Foxo3a activation occurs in some cell lines [59] . ONC201 can also act via TRAIL-independent mechanisms, as demonstrated by the induction of ATF4 that was deleterious in TNBC cells [10] , [58] , [59] .…”

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 75%

“…ONC201 induced antiproliferative effects in both mesenchymal- and epithelial-like triple-negative breast cancer (TNBC) cell lines [59] . Studies have shown that the efficacy of ONC201 in breast cancer, especially TNBC, can involve a number of mechanisms.…”

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 99%

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

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ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

Cited by 32 publications

References 51 publications

ONC201 kills breast cancer cellsin vitroby targeting mitochondria

ONC201 kills breast cancer cellsin vitroby targeting mitochondria

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

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