A Trifluorinated Thiazoline Scaffold Leading to Pro‐apoptotic Agents Targeting Prohibitins

Pérez-Perarnau, Alba; Preciado, Sara; Palmeri, Claudia Mariela; Moncunill-Massaguer, Cristina; Iglesias-Serret, Daniel; González-Gironès, Diana M.; Miguel, Mario; Karasawa, Satoki; Sakamoto, Satoshi; Cosialls, Ana M.; Rubio-Patiño, Camila; Saura-Esteller, José; Ramón, Rosario; Caja, Laia; Fabregat, Isabel; Pons, Gabriel; Handa, Hiroshi; Alberício, Fernando; Gil, Joan; Lavilla, Rodolfo

doi:10.1002/anie.201405758

Cited by 37 publications

(46 citation statements)

References 25 publications

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“…We previously reported that fluorizoline (Figure 1a ) binds specifically to PHB1 and PHB2 [ 2 ]. To examine whether the pro-apoptotic effects of this compound require PHBs, we sought to analyze the response of PHB-deficient cells to fluorizoline treatment.…”

Section: Resultsmentioning

confidence: 99%

“…As apoptosis induction can affect ΔΨm [ 39 ], it was important to analyze ΔΨm before the onset of cell death. To this end, we used Jurkat cells, as previous results from our group showed that cytochrome c was released from mitochondria after 8 h of fluorizoline treatment [ 2 ]. Interestingly, 8 h of fluorizoline treatment resulted only in a slight loss of ΔΨm ( Supplementary Figure 5 ), which suggests that it is a consequence of apoptosis induction.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, there is need for the development of novel apoptosis-inducing compounds as potential therapies for cancer. In a previous report we described the synthesis of a class of small molecules with an unprecedented fluorinated thiazoline scaffold as novel pro-apoptotic compounds [ 2 ]. Interestingly, the diaryl trifluorothiazoline compound 1a (Figure 1a ), hereafter referred to as fluorizoline, triggered apoptosis through a p53-independent mechanism, which is highly relevant as half of all cancers acquire mutations in p53 during the malignant transformation [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the diaryl trifluorothiazoline compound 1a (Figure 1a ), hereafter referred to as fluorizoline, triggered apoptosis through a p53-independent mechanism, which is highly relevant as half of all cancers acquire mutations in p53 during the malignant transformation [ 3 ]. In addition, we identified prohibitin 1 and 2 (PHBs) as proteins selectively binding to fluorizoline [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

et al. 2015

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We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa−/−/Bim−/− MEFs and NOXA-downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

et al. 2015

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“…Prohibitins have been shown to accumulate in response to several stresses, including chemotherapeutic agents, the UPR ER inducer tunicamycin and nutrient starvation, while PHB knock-down sensitized melanoma cells [116]. Several reports suggest PHB proteins as potential druggable targets to halt cancer proliferation and metastasis, while small molecules exhibiting antitumor effects have been shown to target prohibitins [117,118].…”

Section: The Phb Complex Responds To Mitochondrial Stressmentioning

confidence: 99%

Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Hernando‐Rodríguez¹,

Artal‐Sanz²

2018

Preprint

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Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the OXPHOS system for ATP production. It requires, in addition, the import of thousands of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPRmt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial PHB (prohibitin) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

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Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines

Huang

Liu

2020

FEBS Open Bio

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Prohibitin (PHB) is a highly conserved, ubiquitously expressed, multifunctional protein with a well‐characterized function as a chaperone‐stabilizing mitochondrial proteins. Recently it was reported that nuclear PHB participates in HIRA chaperone complexes and regulates downstream gene expression via cell cycle independent deposition of H3.3 into DNA. However, the role of PHB in cancer progression remains controversial with conflicting reports in the literature, perhaps due to its cell type‐dependent subcellular localization. Here, we report that the increased expression of nuclear PHB is positively correlated with metastasis of breast cancer cell lines. We showed PHB participates in the HIRA complex by interacting with HIRA through the linker region of the PHB domain and stabilizes all components of the HIRA complex in breast cancer. Overexpression of nuclear PHB resulted in a higher enrichment of histone H3.3 deposited by the HIRA complex at the promoters of mesenchymal markers. This coincided with an increased gene expression level of these markers, and induced EMT in breast cancer. Overall, these molecular and structural mechanisms suggest that nuclear PHB could hold promise as a potential target for cancer therapy.

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A Trifluorinated Thiazoline Scaffold Leading to Pro‐apoptotic Agents Targeting Prohibitins

Cited by 37 publications

References 25 publications

A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines

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