AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

Abstract

Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34CD38 leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations. JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs. These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer. .

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

“…Moreover, they found that inhibition of the early stage of autophagy reduced the activation of caspase-8 and caspase-3, while the effect of late autophagy inhibition was the opposite [42]. In addition to autophagy, several studies have shown that the activation of AMPK and inhibition of mTOR is closely related to apoptosis [44-47]. In our study, activation of the AMPK-mTOR pathway led to a higher amount of apoptosis, which suggests that the AMPK-mTOR pathway may also contribute to isogambogenic acid-induced apoptosis in glioma cells.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…Expression of helicaselike transcription factor, a member of switch/sucrose non-fermentable family proteins that regulate chromatin/ nucleosome remodeling, promotes DNA damage repair and HCQ resistance, which indicates that HCQ could be combined with DNA repair inhibitors. 170,205 CQ can also kill cancer cells in combination with cell cycle inhibitors. 38,170 What is encouraging is that a relatively low CQ/HCQ concentration (10 lM), in synergy with BET inhibition, is sufficient to cause apoptosis in CSC of both pancreatic cancer and acute myeloid leukemia.…”

“…205,209 However, in leukemia patients, high doses of CQ are needed to inhibit autophagy, which limits their therapeutic efficacy. 205,209 However, in leukemia patients, high doses of CQ are needed to inhibit autophagy, which limits their therapeutic efficacy.…”

“…Consistently, it was shown that CQ induces the secretion of tumor suppressor Par-4 in a p53-dependent manner. 205 Therefore, their clinical application for cancer would be limited unless used in combination with drugs that kill cancer cells with more differentiated features. 258 This effect of CQ would be consistent with autophagy inhibition, because autophagy bestows malignant cells a metabolic flexibility that is essential to survive in niches with limited nutrient availability.…”

“…38,170 What is encouraging is that a relatively low CQ/HCQ concentration (10 lM), in synergy with BET inhibition, is sufficient to cause apoptosis in CSC of both pancreatic cancer and acute myeloid leukemia. 170,205 CQ can also kill cancer cells in combination with cell cycle inhibitors. 206,207 A combination of CQ and proteasome inhibitor causes apoptosis in human liver tumors orthotopically or subcutaneously xenografted in mice.…”