PXD015141

PXD015141 is an original dataset announced via ProteomeXchange.

Title	Marizomib eradicates primary and metastatic triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition
Description	Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive, metastatic, and clinically challenging breast cancer subtype with worst prognosis. Despite survival dependency on the proteasome pathway genes, the FDA-approved proteasome inhibitors induced minimal clinical response in TNBC patients due to weaker proteasome inhibition. Here, we show that a novel proteasome inhibitor Marizomib (Mzb), inhibited multiple proteasome catalytic activities and induced better anti-tumor response in TNBC cell line and patient-derived xenografts alone and in combination with a standard-of-care chemotherapy, doxorubicin. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Development of metastatic disease, especially brain metastasis, remains a reason for a greater mortality rate amongst TNBC patients. Mzb reduces lung and brain metastasis in vivo by reducing circulating tumor cells and the expression of multiple epithelial-to-mesenchymal genes. We also demonstrate that Mzb-induced OXPHOS inhibition upregulates glycolysis to fulfill the metabolic demand of TNBC cells and hence, combined inhibition of glycolysis with Mzb leads to a synergistic anti-cancer activity in vivo. Collectively, our data provide a strong rationale for the clinical evaluation of Mzb in primary and metastatic TNBC patients.
HostingRepository	PRIDE
AnnounceDate	2020-05-26
AnnouncementXML	Submission_2020-05-26_15:12:11.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Prahlad Raninga
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-23 06:04:31	ID requested
⏵ 1	2020-05-26 15:12:12	announced

Raninga PV, Lee A, Sinha D, Dong LF, Datta KK, Lu X, Kalita-de Croft P, Dutt M, Hill M, Pouliot N, Gowda H, Kalimutho M, Neuzil J, Khanna KK, Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition. Theranostics, 10(12):5259-5275(2020) [pubmed]

submitter keyword: Marizomib, TNBC, OXPHOS, proteomics

Kum Kum Khanna
contact affiliation	QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane QLD 4006, Australia
contact email	KumKum.Khanna@qimrberghofer.edu.au
lab head
Prahlad Raninga
contact affiliation	QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane QLD 4006
contact email	Prahlad.Raninga@qimrberghofer.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015141
     1. Label: PRIDE project
     2. Name: Marizomib eradicates primary and metastatic triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition