Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia

Abstract

Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML.

Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia

“… Enzyme Enzyme description Inhibitor Anti-AML effect in pre-clinic research Ref. ACC A key enzyme that catalyzes the conversion of acetyl-CoA to malonyl-CoA TOFA Impairing primary human AML cells viability, synergistically inducing IDH1-mutant primary cell death with ivosidenib [ 106 ] ACLY A cytosolic enzyme that catalyzes the generation of acetyl-CoA from citrate SB-204990 Significantly reducing the proliferation of MOLM-13 and THP-1 cell lines [ 102 ] CPT1 A key enzyme that catalyzes the rate-limiting step of FAO Etomoxir Exhibiting synergistic inhibitory effects with Ara-C on AML [ 100 ] Avocatin B Synergistically enhancing ROS production and inducing apoptosis in AML cells with Ara-C [ 107 ] ST1326 Exhibiting synergistic inhibitory effects with Bcl-2 inhibitor ABT199 on AML [ 108 ] FASN The only human lipogenic enzyme available for de novo fatty acid synthesis Orlistat Exhibiting synergistic effect in promoting apoptosis in AML cells with CFZ [ 109 ] TVB-3166 Exhibiting synergistic effect in promoting apoptosis in AML cells with CFZ [ 109 ] HMGCR A key enzyme in the cholesterol biosynthesis pathway Atorvastatin Inhibiting endocytosis/pinocytosis in statin-sensitive primary human AML specimens [ 110 ] Simvastatin Blocking the chemotherapy-induced enhancement of HMGCR carrying sEVs secretion in AML cells [ 111 ] VLCAD An enzyme involved in the breakdown of long-chain fatty acids AYNE Suppressing FAO and mitochondrial respiration, resulting in selective AML cell death [ 98 ] ACC acetyl-CoA carboxylase, ACLY ATP-citrate lyase, Ara-C cytarabine, AYNE avocadyn...…”

TP53 signal pathway confers potential therapy target in acute myeloid leukemia

“…It suggested that AML response to statins by Vesicular trafficking. 56 4.2 | Targeting the P53 signal pathway…”

“…Patients with mut‐p53 and wild‐type p53 malignancies including AML are recruiting (NCT03560882). It suggested that AML response to statins by Vesicular trafficking 56 …”

Disputable questions of statins antitumor effects in hemoblastoses

“…Статины оказывали цитотоксический и антипролифе ративный эффект на линии клеток NKклеточного лимфобластного лейкоза за счет ингибирования гера нилгеранилдифосфата [27]. Кроме этого, статины по давляют жизнеспособность клеток ОЛЛ за счет нару шения везикулярного транспорта, который нуждается в координации белками, подвергающимися модифи кации с помощью геранилгеранилирования [28].…”

“…Одним из механизмов химиорезистентности ОМЛ оказался гомеостаз холе стерина. Поэтому комплексное применение статинов в лечении ОМЛ, вероятно, могло бы позволить прео долеть лекарственную устойчивость, равно как это достигается при использовании эпигенетических аген тов [28,33]. В эксперименте на культуре ОМЛ было показано, что симвастатин действует синергетически с ингибитором MEK AZD6244, подавляя пролифе рацию клеток значительно сильнее, чем монотерапия препаратом AZD6244 [26].…”