Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Tsalikis, Jessica; Abdel-Nour, Mena; Farahvash, Armin; Sorbara, Matthew T.; Poon, Stephanie; Philpott, Dana J.; Girardin, Stephen E.

doi:10.1128/mcb.00489-18

Cited by 37 publications

(45 citation statements)

References 54 publications

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“…These authors also detected increased polyA site readthrough in IGG treated cells further suggesting that a fundamental problem in transcription and co-transcriptional processing may underlie some of the unique biological effects of IGG [21]. It is noteworthy that these authors still detected a defect in pre-mRNA splicing using RNA-seq analysis in this and previous papers [21,23,24] Lastly, IGG also appeared to inhibit trafficking of the amyloid precursor protein (APP) from endoplasmic reticulum (ER) to the Golgi [24]and lysosome-mediated turnover [13]. In the former, APP levels increased in response to IGG but not the SF3B1 inhibitor spliceostatin [24].…”

Section: Discussionmentioning

confidence: 61%

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

Vanzyl

Sayed

Blackmore

et al. 2019

Preprint

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21The spliceosome assembles on pre-mRNA in a stepwise manner through five successive 22 pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to 23 generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the 24 spliceosome have been identified and they are cytotoxic. However, little is known about the 25 mechanisms leading to cell death. Activating transcription factor 3 (ATF3) is a transcription 26 factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, 27ATF3 protein levels increased in cultured human and mouse cells in response to cytotoxic levels 28 of the two splicing inhibitors tested: pladienolide B (PB) and isoginkgetin (IGG), that target 29 different pre-spliceosome complexes. Importantly, deletion of ATF3 protected mouse embryonic 30 fibroblasts to these splicing inhibitors. Our results indicate that both splicing inhibitors activate 31 ATF3, and that ATF3 is contributing to the sensitivity of MEFs to these compounds. 32 33 42 sites, the branch sequence, and polypyrimidine tract, leading to the assembly of a functional 43 spliceosome through the E, A, B, B* and C pre-spliceosome complexes[2]. 44 A variety of small molecules interfere with the spliceosome at distinct points in assembly. 45 PB is a spliceosome inhibitor derived from Streptomyces platensis that targets the SF3B1 46 protein. This protein is a component of the U2 snRNP complex so PB prevents the formation of 47 the A complex[3]. IGG is a natural compound derived from Ginkgo biloba, that affects the 48 spliceosome at a subsequent step, preventing the transition from the A to the B complex by 49 inhibiting the stable binding of the U4/U5/U6 tri-snRNP complex[4]. These two compounds 50 affect a different stage of spliceosome formation, however both have been shown to decrease cell 51 viability through uncharacterized mechanisms [5, 6]. 52 Activating transcription factor 3 (ATF3) is a member of the ATF/CREB transcription 53 factor family and is activated in response to a variety of stresses including DNA damage, 54 inflammation, endoplasmic reticulum (ER) stress and oxidative stress [7-10]. ATF3 has been 55 shown to have a variety of functions, one of which is regulating the expression of proapoptotic 56 genes, such as GADD153/CHOP[11]. We sought to determine if ATF3 plays a role in sensitivity 57 to the inhibition of pre-mRNA splicing. Here we report that ATF3 is induced in human and 58 mouse cells and that deletion of ATF3 in mouse embryonic fibroblasts (MEFs) protects cells 59 from the lethal effects of spliceosome inhibitors. This work provides important insight into the 60 mechanisms underlying the cell death induced by spliceosome dysfunction.

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Section: Discussionmentioning

confidence: 61%

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

Vanzyl

Sayed

Blackmore

et al. 2019

Preprint

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“…For example, isoginkgetin efficiently inhibits the splicing of SMN2 (survival of motor neuron 2) mRNA [ 98 ]. However, isoginkgetin exerts multiple cellular effects, being also a proteasome inhibitor [ 99 ] and a transcription modulator, modifying RNA polymerase elongation rates [ 100 ]. In contrast, HNK has no major effect on transcription and is a more potent biflavonoid modulator of splicing than isoginkgetin (and amentoflavone did not alter splicing in vitro) [ 89 ].…”

Section: Hnk: a Senp1 Protease Inhibitor Modulating Pre-mrna Splicingmentioning

confidence: 99%

“…Other biflavonoids have revealed interesting anticancer properties recently, such as robustaflavone [ 111 ], isoginkgetin [ 99 ], japoflavone D [ 112 ], sumaflavone [ 113 ] and cupressuflavone [ 113 , 114 ], but these C–C-type biflavonoids will not be further discussed here.…”

Section: Anticancer Activities and Mechanism Of Action Of Hnk Analogumentioning

confidence: 99%

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

Goossens

Bailly

2021

Nat. Prod. Bioprospect.

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Biflavonoids are divided in two classes: C–C type compounds represented by the dimeric compound amentoflavone and C–O–C-type compounds typified by hinokiflavone (HNK) with an ether linkage between the two connected apigenin units. This later sub-group of bisflavonyl ethers includes HNK, ochnaflavone, delicaflavone and a few other dimeric compounds, found in a variety of plants, notably Selaginella species. A comprehensive review of the anticancer properties and mechanism of action of HNK is provided, to highlight the anti-proliferative and anti-metastatic activities of HNK and derivatives, and HNK-containing plant extracts. The anticancer effects rely on the capacity of HNK to interfere with the ERK1-2/p38/NFκB signaling pathway and the regulation of the expression of the matrix metalloproteinases MMP-2 and MMP-9 (with a potential direct binding to MMP-9). In addition, HNK was found to function as a potent modulator of pre-mRNA splicing, inhibiting the SUMO-specific protease SENP1. As such, HNK represents a rare SENP1 inhibitor of natural origin and a scaffold to design synthetic compounds. Oral formulations of HNK have been elaborated to enhance its solubility, to facilitate the compound delivery and to enhance its anticancer efficacy. The review shed light on the anticancer potential of C–O–C-type biflavonoids and specifically on the pharmacological profile of HNK. This compound deserves further attention as a regulator of pre-mRNA splicing, useful to treat cancers (in particular hepatocellular carcinoma) and other human pathologies.

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“…Lastly, IGG also appeared to inhibit trafficking of the amyloid precursor protein (APP) from endoplasmic reticulum (ER) to the Golgi [24] and lysosome-mediated turnover [13]. In the former, APP levels increased in response to IGG but not the SF3B1 inhibitor spliceostatin [24].…”

Section: Plos Onementioning

confidence: 99%

“…APP was retained in the ER where the protein was stable and accumulated [24]. In the latter paper [13], IGG led to increased lysosomal stress, increased TFEB protein expression (a regulator of lysosomal biogenesis) and the accumulation of polyubiquitinated proteins under nutrient starving conditions suggesting that IGG may be inhibiting proteasomes and altering lysosomal function under some conditions [13]. Intriguingly, IGG-induced TFEB activated ATF3 indirectly through ATF4, however it was unclear if ATF3 contributed to cell death detected in this manuscript.…”

Section: Plos Onementioning

confidence: 99%

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

et al. 2020

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The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.

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Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Cited by 37 publications

References 54 publications

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

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