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 (human)

SUBMITTER: Kelsey Fisher-Wellman 

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

REPOSITORIES: jPOST