PXD025645

PXD025645 is an original dataset announced via ProteomeXchange.

Title	Vincristine resistance reshapes sphingolipid composition and promotes mitochondrial complex I deficiency in acute myelogenous leukemia
Description	Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. Vinca alkaloids such as vincristine (VCR), widely used in cancer treatment, are no exception, as their beneficial actions are often supplanted by resistance. In the present work we utilized HL-60 human leukemia cells and a VCR-resistant counterpart, HL-60/VCR cells, to determine whether VCR resistance affected alterations in SL composition and mitochondrial bioenergetics supportive of a neoplastic phenotype. HL-60/VCR cells, as opposed to wild-type cells, showed striking increases in sphingosine 1-phosphate (S1P) supportive of mitogenicity and disease dissemination. VCR resistance was also characterized by increases in ceramides as well as glucosylceramides (GC), and decreases in levels of sphingomyelin. Immunoblot analysis revealed upregulated expression of sphingosine kinase (SPHK1), which catalyzes formation of S1P, glucosylceramide synthase, which catalyzes formation of GC, and acid ceramidase, responsible for ceramide hydrolysis. With respect to mitochondria, despite increased basal respiration in VCR cells, direct interrogation of the VCR mitochondrial network revealed intrinsic respiratory complex insufficiency, largely localized to complex I (CI). Importantly, intrinsic CI limitations were completely masked using traditional intact cell respirometry, thus highlighting the critical importance of comprehensive bioenergetic phenotyping to elucidate metabolic remodeling in drug resistance. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against VCR resistance.
HostingRepository	jPOST
AnnounceDate	2022-04-21
AnnouncementXML	Submission_2022-09-18_03:48:04.670.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kelsey Fisher-Wellman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; L-methionine sulfoxide; TMT6plex reporter+balance reagent N-acylated residue; TMT6plex reporter+balance reagent acylated N-terminal
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-26 11:51:18	ID requested
1	2022-04-21 10:08:50	announced
⏵ 2	2022-09-18 03:48:05	announced	2022-09-18: Updated FTP location.

Fisher-Wellman KH, Hagen JT, Kassai M, Kao LP, Nelson MAM, McLaughlin KL, Coalson HS, Fox TE, Tan SF, Feith DJ, Kester M, Loughran TP, Claxton DF, Cabot MC, Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia. FASEB J, 36(1):e22094(2022) [pubmed]

submitter keyword: Vincristine, drug resistance, AML, mitochondria, sphingolipids

Kelsey Fisher-Wellman
lab head
Kelsey Fisher-Wellman
contact affiliation	East Carolina Diabetes and Obesity Institute
dataset submitter

jPOST dataset URI

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