Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia.

Autor: Gianni' M; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy., Goracci L; Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, 06123, Perugia, Italy., Schlaefli A; Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008, Bern, Switzerland., Di Veroli A; Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, 06123, Perugia, Italy., Kurosaki M; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy., Guarrera L; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy., Bolis M; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy.; Functional Cancer Genomics Laboratory, Institute of Oncology Research, USI, University of Southern Switzerland, 6500, Bellinzona, Switzerland.; Bioinformatics Core Unit Institute of Oncology Research, Swiss Institute of Bioinformatics, 1000, Lausanne, Switzerland., Foglia M; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy., Lupi M; Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, via Mario Negri 2, 20156, Milano, Italy., Tschan MP; Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008, Bern, Switzerland., Cruciani G; Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, 06123, Perugia, Italy., Terao M; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy., Garattini E; Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milano, Italy. enrico.garattini@marionegri.it.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Jan 10; Vol. 13 (1), pp. 30. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41419-021-04476-z
Abstrakt: The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.
(© 2021. The Author(s).)
Databáze: MEDLINE
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