Proteomics

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Vincristine resistance reshapes sphingolipid composition and promotes mitochondrial complex I deficiency in acute myelogenous leukemia


ABSTRACT: 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Kelsey Fisher-Wellman 

PROVIDER: PXD025645 | JPOST Repository | Thu Apr 21 00:00:00 BST 2022

REPOSITORIES: jPOST

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Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.

Fisher-Wellman Kelsey H KH   Hagen James T JT   Kassai Miki M   Kao Li-Pin LP   Nelson Margaret A M MAM   McLaughlin Kelsey L KL   Coalson Hannah S HS   Fox Todd E TE   Tan Su-Fern SF   Feith David J DJ   Kester Mark M   Loughran Thomas P TP   Claxton David F DF   Cabot Myles C MC  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20220101 1


Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistan  ...[more]

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