Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism

Lee, Ji-Young; Yesilkanal, Ali E.; Wynne, Joseph; Frankenberger, Casey; Liu, Juan; Yan, Jielin; Elbaz, Mohamad; Rabe, Daniel C.; Rustandy, Felicia D; Tiwari, Payal; Grossman, Ellie; Hart, Peter C.; Kang, Changdon; Sanderson, Sydney M.; Andrade, Jorge; Nomura, Daniel K.; Bonini, Marcelo G.; Locasale, Jason W.; Rosner, Marsha Rich

doi:10.1038/s41586-019-1005-x

Cited by 280 publications

(295 citation statements)

References 49 publications

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“…Metformin (MET) is the first‐line antidiabetogenic drug for treatment of type 2 diabetes . More than that, MET was broadly reported for its anticancer effect in recent years . Besides, MET is able to protect the liver against chemical or viral hepatotoxicants .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Sun

Zhai²,

et al. 2019

Cancer Medicine

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Hepatocellular carcinoma (HCC) is a devastating and highly metastatic cancer worldwide. Metformin (MET) is the priority drug for treatment of type 2 diabetes; however, it possesses multiple biological effects like anticancer and hepatoprotective activity. Herein, we examined the effects of aloin (barbaloin) and MET as well as combination treatment in HCC cell line in vitro and in vivo. As a result, aloin and MET alone exhibited inhibitory effects on proliferation and invasion of HepG2 and Bel‐7402 cells. Specially, combination treatment of aloin and MET showed enhanced inhibitory effects in vitro. Aloin and MET alone induced apoptosis and autophagy in vitro. Similarly, aloin and MET cooperated to promote apoptosis and autophagy in HepG2 and Bel‐7402 cells. In the HepG2 xenograft models, aloin in combination with MET confine tumor growth and facilitate apoptosis and autophagy. Both the in vitro and in vivo results showed that aloin and MET alone as well as combination treatment activated the PI3K/AKT/mTOR pathway. Overall, our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Sun

Zhai²,

et al. 2019

Cancer Medicine

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“…1E and 2A). Our previous work similarly showed that reducing BACH1 expression in TNBC increased oxidative phosphorylation in mitochondria, mirroring the RKIP phenotype 25 . This prompted us to investigate whether BACH1 is responsible for regulating motility-related gene targets of RKIP as well.…”

Section: Rkip Regulates a Clinically Relevant Set Of Motility-relatedmentioning

confidence: 65%

“…Drugs such as these, when used as single agents, have not given durable responses thereby necessitating multi-drug approaches (e.g. 45 BACH1, which we recently identified as an inhibitor of mitochondrial metabolism that can be targeted independently in ~30% of breast tumors 25 , is shown here to be a transcriptionally-regulated and pro-invasive mediator of the stress MAPK network.…”

Section: Discussionmentioning

confidence: 94%

Limited inhibition of multiple nodes in a driver network blocks metastasis

Yesilkanal

Yang

Tiwari

et al. 2020

Preprint

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Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stressregulated MAP kinase network activity, reducing the output to metastatic transcription factor BACH1 and motilityrelated target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for antimetastatic treatment.

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“…We previously reported that BACH1 promotes the proliferation of MEFs transformed with H-Ras v12 and their tumor formation in a mouse transplantation model (Nakanome et al, 2013). Recently, BACH1 was found to promote the proliferation and/or metastasis of breast cancer and ovarian cancer cells (Han et al, 2019, Lee et al, 2014, Lee et al, 2019, Mansoori et al, 2019). BACH1 is therefore considered to have dual functions in cancers: promoting cell proliferation and cell death through ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1

Nishizawa

Matsumoto

Shindo

et al. 2019

Preprint

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1Ferroptosis is an iron-dependent programmed cell death resulting from alterations of 2 metabolic processes. However, its regulation and physiological significance remain to be 3 elucidated. By analyzing transcriptional responses of murine embryonic fibroblasts 4 exposed to the ferroptosis-inducer erastin, we found that a set of genes related to oxidative 5 stress protection was induced upon ferroptosis. We further showed that the transcription 6 factor BACH1 promoted ferroptosis by repressing the expression of a subset of 7 erastin-inducible genes involved in the synthesis of glutathione or metabolism of 8 intracellular labile iron, including Gclm, Gclc, Slc7a11, Hmox1, Fth1, Ftl1, and Slc40a1. 9 Compared with wild-type mice, Bach1 -/mice showed resistance to myocardial infarction, 10

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Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism

Cited by 280 publications

References 49 publications

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Limited inhibition of multiple nodes in a driver network blocks metastasis

Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1

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