The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation

Abstract

AML is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione and multiple TCA metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, that binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed and relapsed patients, while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.

Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death

“…We hypothesized that this reprogramming might be partly responsible for the decrease in reactive ferrous iron–induced oxidative damage to cisplatin-resistant cells. As expected, we observed that glutamine deprivation induced lipid peroxidation and decreased GSH levels in both cell lines, which was consistent with a report that inhibition of glutamine uptake targeting solute carrier family 1, member A5 (SLC1A5) reduced GSH levels, Krebs cycle activity, and inhibition of OXPHOS in leukemia stem cells ( 58 ). To take advantage of this iron metabolism reprogramming ability, we investigated whether DFO could suppress the growth of cisplatin-resistant A549/DDP cells.…”

SB939 is analyzed by STAT3 to inhibit breast cancer cell metastasis-related genes

“…Signal transducer and activator of transcription 3 (STAT3), one of the seven members of the STAT family, is responsible for transcriptional regulation of the cell cycle in normal cells but is activated in different breast cancer types, playing a role in promoting tumor growth [28]. It is well documented that STAT3 is highly expressed in triple-negative breast cancers and is involved in tumor metastasis and invasion.STAT3 typically undergoes upstream signaling to activate phosphorylation of tyrosine and serine residues and subsequently induces dimerization between two STAT3 molecules through phosphotyrosine-SH2 (Src homologous structural domain 2) interactions [27]. The activated STAT3 dimer subsequently translocates to the nucleus and binds to its target gene to function as a transcriptional agent.…”

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

“… 48 Most leukemia and lymphomas overexpress SLC1A5 to take up more glutamine to sustain proliferation, 43,47,49 leading to poor prognosis 39 . The expression of SLC1A5 can be upregulated by the signal transducer and activator of transcription 3–MYC proto‐oncogene axis in acute myeloid leukemia (AML) stem and progenitor cells, increasing glutamine influx in leukemia stem cells (LSCs) to prolong tumor survival 50 . Abnormal activation of MYC in Burkitt's lymphoma significantly upregulates the expression of both SLC1A5 and SLC7A5, triggering cellular dependence on glutamine for growth and survival 51–54 .…”

“…39 The expression of SLC1A5 can be upregulated by the signal transducer and activator of transcription 3-MYC protooncogene axis in acute myeloid leukemia (AML) stem and progenitor cells, increasing glutamine influx in leukemia stem cells (LSCs) to prolong tumor survival. 50 Abnormal activation of MYC in Burkitt's lymphoma significantly upregulates the expression of both SLC1A5 and SLC7A5, triggering cellular dependence on glutamine for growth and survival. [51][52][53][54] Exchanging glutamine and leucine via SLC7A5 can activate mTORC1 pathway, a central regulator of cell growth crucial in hematological malignancies.…”