Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop

Abstract

Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…Cancer triggers metabolism, angiogenesis, and erythropoiesis to counteract the disadvantages of hypoxia, of which HIF-1 is the central regulatory mechanism of hypoxia that acts by upregulating its downstream genes (216,217). HIF-1 is the main transcription factor that induces the expression of almost all genes encoding glucose transporters and glycolytic key enzymes (218,219), which allows hypoxic cancer cells to absorb glucose more efficiently, metabolize pyruvate to lactate, activate multi-drug resistance gene, and induce chemoresistance (220,221). Hypoxia has synergistic effects with acidosis on inducing chemoresistance by upregulating the expression of fatty acid synthase and regulating lipid metabolism (209); it can induce acidosis by selecting glycolytic cells, and acidosis can further select cells with upregulated glycolysis and acidic resistance, thereby choosing cells with survival advantages (222).…”

Characterization of a novel glucocorticoid-resistant human B-cell acute lymphoblastic leukemia cell line, with AMPK, mTOR and fatty acid synthesis pathway inhibition

“…Initially, most researchers reported that mTOR signaling activation may contribute to chemoresistance and ALL progression [ 17 , 23 , 54 ]. On the contrary, a recent paper showed that activation of mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches [ 55 ]. It is intriguing that while AMPK functions as an antagonist of mTOR [ 56 ]; both AMPK and mTOR signaling pathways were inhibited in NALM-6/HDR cells, which is consistent with the findings in CEM-C7/HDR [ 6 ].…”

Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses

“…T-ALL switch their metabolic programs in a similar way to normal HSCs when cultured in low oxygen [200]. Reduced mitochondrial activity and cell cycle progression in these low oxygen niches increases glycolysis and lowers their sensitivity to vincristine and cytarabine (cell cycle-related drugs) and dexamethasone, compared with T-ALL cells grown under normoxic conditions [201]. While low oxygen levels suppressed the activity of mTORC1, it increased the activity of HIF1α with the concomitant increase in the expression of HIF1α effector genes such as, VEGF, GLUT3 and CXCR4 to reduce mitochondrial activity and as such ROS levels in ALL [201].…”