The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism

Choucair, Hassan; Rahman, Khalilur; Umashankar, Balasubrahmanyam; Al-Zubaidi, Yassir; Bourget, Kirsi; Chen, Yongjuan; Dunstan, Colin R.; Rawling, Tristan; Murray, Michael T.

doi:10.1016/j.canlet.2021.11.022

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…A strong and lasting ER stress response creates an imbalance in Ca 2+ . ER stress is known to involve the endoplasmic reticulum kinase (PERK) pathway, [7][8][9] the inositol-requiring enzyme1 (IRE1) pathway [10][11][12] and the activating transcription factor 6 (ATF-6) pathway. 13,14 As the key site of energy transformation, the mitochondria also represent the main regulatory site for apoptosis and also play a key role in most of the regulatory processes related to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway

Wang

et al. 2022

Cancer Medicine

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Section: Introductionmentioning

confidence: 99%

“…A strong and lasting ER stress response creates an imbalance in Ca 2+ . ER stress is known to involve the endoplasmic reticulum kinase (PERK) pathway, 7 , 8 , 9 the inositol‐requiring enzyme1 (IRE1) pathway 10 , 11 , 12 and the activating transcription factor 6 (ATF‐6) pathway. 13 , 14 …”

Section: Introductionmentioning

confidence: 99%

Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway

Wang

et al. 2022

Cancer Medicine

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“…These findings imply that 6-ME can induce the activation of JNK-ERK/MAPK to trigger subsequent apoptosis in OC cells. Mitochondria are one of the main sources of cellular ROS production, and mitochondrial disruption can often occur during cancer development and treatment (Choucair et al, 2022;Dakik et al, 2022;Liu et al, 2022). We speculated that 6-ME-induced OC cell apoptosis is due to its involvement in triggering signals for ROS production and accumulation.…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis

et al. 2023

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Introduction: Alkaloids derived from M. cordata (Papaveraceae family), have been found to display antineoplastic activity in several types of cancer. However, the antitumor effects and mechanisms of a new alkaloid extracted from the fruits of M. cordata, named 6-Methoxydihydroavicine (6-ME), remains unclear in the case of ovarian cancer (OC).Methods: CCK-8 assay was employed to analyze the cell viabilities of OC cells. RTCA, and colony-formation assays were performed to measure OC cell growth. Alterations in apoptosis and ROS levels were detected by flow cytometry in accordance with the instructions of corresponding assay kits. A Seahorse XFe96 was executed conducted to confirm the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect alterations in target proteins. The subcutaneous xenografted tumor model of OC was used to further validate the anti-tumor activity of 6-ME in vivo.Results: Here, we reported for the first time that 6-ME inhibits OC cells growth in vitro and in vivo. Meanwhile, we found that 6-ME showed great antineoplastic activities by disrupting mitochondria homeostasis and promoting apoptosis in OC cells. Further investigation of the upstream signaling of apoptosis revealed that 6-ME-triggered apoptosis was induced by reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) activation and mitochondria dysfunction in OC cells. Furthermore, we found oxaloacetic acid (OAA), a crucial metabolite has been proved to be related to NADPH production, can block the cytotoxicity and accumulation of ROS caused by 6-ME in OC cells.Discussion: In summary, our data show that 6-ME exhibits cytotoxicity to OC cells in a ROS-dependent manner by interrupting mitochondrial respiration homeostasis and inducing MAPK-mediated apoptosis. This evidence suggests that 6-ME is a promising remedy for OC intervention.

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“…Therefore, it is reasonable to suggest that S63845, by binding the region of MCL-1 normally occupied by NOXA, can prevent the formation of MCL-1:NOXA complexes leading to NOXA degradation and stabilization of MCL-1. Various factors influencing the NOXA level in solid cancer have been identified [93,94], however, the impact of MCL-1 synthetic inhibitor has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal

Hartman,

Koziej,

Kluszczyńska

et al. 2023

Cancers

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Background: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins. Reversible alterations were found in MCL-1 levels and MCL-1 inhibitors, BIM and NOXA. Taking advantage of melanoma cell dependency on MCL-1 for survival, we used S63845. While it was designed to inhibit MCL-1 activity, we showed that it also significantly reduced NOXA levels. S63845-induced apoptosis was detected as the enhancement of Annexin V-positivity, caspase-3/7 activation and histone H2AX phosphorylation. Percentages of Annexin V-positive cells were increased most efficiently in trametinib-resistant melanoma cells displaying the p-ERK1/2low/MCL-1low/BIMhigh/NOXAlow phenotype with EC50 values at concentrations as low as 0.1 μM. Higher ERK1/2 activity associated with increased MCL-1 level and reduced BIM level limited pro-apoptotic activity of S63845 further influenced by a NOXA level. Conclusions: Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy.

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The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism

Cited by 11 publications

References 41 publications

Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway

Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway

A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal

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The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism

Cited by 11 publications

References 41 publications

Apoptin causes apoptosis inHepG‐2 cells via Ca2+imbalance and activation of the mitochondrial apoptotic pathway

Apoptin causes apoptosis inHepG‐2 cells via Ca2+imbalance and activation of the mitochondrial apoptotic pathway

A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal

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Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway

Apoptin causes apoptosis inHepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway