Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Raninga, Prahlad; Lee, A.; Sinha, Debottam; Dong, Lan-Feng; Datta, Keshava K.; Lu, Xinquan; Croft, Priyakshi Kalita-de; Dutt, Mriga; Hill, Michelle M.; Pouliot, Normand; Gowda, Harsha; Kalimutho, Murugan; Neužil, Jiřı́; Khanna, Kum Kum

doi:10.1101/801720

Cited by 4 publications

(4 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TNBC patients often have a poor disease prognosis due to the metastasis, which mainly occurs in the lungs 6 , 35 . We further analyzed the effect of flubendazole on MDA-MB-231 cell migration by scratch assay and as a result, we found that wound closure ratio was decreased in cells treated with flubendazole (Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

Zhen¹,

Zhao²,

Wang³

et al. 2020

Theranostics

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC) is one of the most prevalent neoplastic diseases worldwide, but efficacious treatments for this pathological condition are still challenging. The lack of an effective targeted therapy also leads to a poor prognosis for patients affected by TNBC. In the present study, we repurposed the distinctive inhibitory effects of flubendazole, a traditional anthelmintic drug, towards the putative modulation of proliferation and migration of TNBC in vitro and in vivo . Methods: According to a series of experimental approaches, including immunofluorescence (IF), immunoblotting (IB), siRNA and GFP-mRFP-LC3 plasmid transfection, respectively, we have found that flubendazole is capable of inducing autophagic cell death and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. The therapeutic effects of flubendazole were evaluated by xenograft mouse models, followed by immunohistochemistry (IHC), IF and IB. Changes in the gene expression profiles of flubendazole-treated TNBC cells were analyzed by RNA sequencing (RNA-seq) and validated by IB. The potential binding mode of flubendazole and EVA1A was predicted by molecular docking and demonstrated by site-directed mutagenesis. Results: We have presently found that flubendazole exhibits a considerable anti-proliferative activity in vitro and in vivo . Mechanistically, the induction of autophagic cell death appears to be pivotal for flubendazole-mediated growth inhibition of TNBC cells, whereas blocking autophagy was able to improve the survival rate and migration ability of flubendazole-treated TNBC cells. Specifically, RNA-seq analysis showed that flubendazole treatment could promote the up-regulation of EVA1A. Flubendazole may regulate autophagy and apoptosis by targeting EVA1A, thus affecting the mechanisms of TNBC proliferation and migration. Furthermore, Thr113 may be the key amino acid residues for the binding of flubendazole to EVA1A. Conclusion: Our results provide novel insights towards the putative anti-cancer efficacy of flubendazole. Furthermore, here we show that flubendazole could serve as a potential therapeutic drug in TNBC. Altogether, this study highlights the possibility of this repurposed autophagic inducer for future cancer treatments.

show abstract

Section: Resultsmentioning

confidence: 99%

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

Zhen¹,

Zhao²,

Wang³

et al. 2020

Theranostics

View full text Add to dashboard Cite

show abstract

“…These surviving cells show high sensitivity to OXPHOS inhibitors, which can block tumor recurrence. Furthermore, marizomib, a dual inhibitor of the proteasome and OXPHOS, reduces lung and brain metastases in patients with triple‐negative breast cancer [30]. In AML, cytarabine‐induced chemo‐resistant cells display high levels of ROS and retain active polarized mitochondria, consistent with a high OXPHOS status.…”

Section: Discussionmentioning

confidence: 99%

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation

et al. 2022

View full text Add to dashboard Cite

Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC‐recurrence‐related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low‐ and high‐risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.

show abstract

“…CryabWt and CryabTg MEFs were treated for 1h at 43ºC to generate heat-shock stress before processing samples in triplicates for in-situ protein digestion as per previously described method 30 . For mass-spectrometry samples were loaded on to a Waters M-Class SYM100 trap column (180 um x 20 mm ID) for 6 min at a flow rate of 5 ul/min with 95% Solvent A (0.1% FA in water), and subsequently separated on a Waters BEH130 analytical column (75 um x 200 mm ID).…”

Section: Mass-spectrometrymentioning

confidence: 99%

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

Rashidieh

Bain

Tria

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have reported tumor suppressor or tumor promoter (oncogene) roles for αB-Crystallin depending on cellular context and environmental conditions. To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model. This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed mouse embryonic fibroblasts (MEFs), we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3. Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

show abstract

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Cited by 4 publications

References 55 publications

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

Contact Info

Product

Resources

About