ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells

Abstract

The bone marrow microenvironment facilitates the proliferation and survival of leukemia cells, contributing to disease relapse. Bone marrow-derived mesenchymal stem cells (MSCs) are well known to promote cancer chemoresistance via soluble factors and cell adhesion. However, little is known about the effects of MSCs on the mitochondrial dynamics of T-cell acute lymphoblastic leukemia (T-ALL) cells, or how this may influence the chemoresistance of these cells. Here, we tested both indirect (Transwell) and direct coculture strategies, and found that MSCs protected T-ALL cells from chemotherapeutic cell death and cytotoxicity under both culture conditions. In addition, cell viability was higher in the direct contact system compared with the Transwell system. We further showed that exposure of T-ALL cells to MSCs decreased mitochondrial reactive oxygen species (ROS) levels and promoted a pro-glycolytic shift that was characterized by increased glucose uptake and lactate production with concomitant reductions in adenosine triphosphate production and mitochondrial membrane potential. In T-ALL cells cocultured with MSCs, the mitochondrial morphology of T-ALL cells were altered from elongation to fragmentation because of the extracellular signal-regulated kinase activation-mediated phosphorylation of the pro-fission factor, dynamin-related protein 1 (Drp1), at residue S616. Consistent with this, the expression of S616-phosphorylated Drp1 recapitulated the mitochondrial dynamics, mitochondrial ROS levels, metabolic switching and chemoresistance seen in T-ALL cells cocultured with MSCs. These findings suggest that the ability of MSCs to trigger Drp1 activation-induced changes in mitochondrial dynamics is crucial to their ability to protect cells against chemotherapeutic agents.

microRNA-488 inhibits chemoresistance of ovarian cancer cells by targeting Six1 and mitochondrial function

“…Our results showed that miR-488 induced mitochondrial fusion, with downregulation of p-Drp1 and Fis1. Drp1 phosphorylation and Fis1 upregulation promotes their mitochondrial membrane localization and induces mitochondrial fission [ 28 ], which was in accord with fragmented mitochondrial shape. Drp1-dependent mitochondrial dynamics may confer either apoptosis or resistance.…”

“…Six1 has been reported to activate ERK signaling in several cancers [ 38 , 39 ]. It has been reported that activation of ERK signaling could lead to Drp-1 phosphorylation and mitochondrial fission, which is involved in the drug resistance of leukemia cells [ 28 ]. Thus Six1 may induce mitochondrial fission through ERK/Drp1 signaling.…”

Metabolic Plasticity in Chemotherapy Resistance

“…Drp1 is a GTPase that regulates mitochondrial fission. Leukemia cells overexpressing wild-type Drp1 or Drp1 S616E presented fragmented mitochondria, reduced mitochondrial ROS levels, increased glycolysis, and improved drug resistance (299)(300)(301). Drp1 S616 phosphorylation through the stimulation of mitochondria fission and glycolysis seemed required to RAS-induced transformation (302).…”

The molecular mechanisms of chemoresistance in cancers

“…Reportedly, src-mediated phosphorylation of Caveolin-1 at Y14 was essential for EGFR activation or its interaction with β1 integrin promoted Fyn-dependent Src homology and Erk1/2 phosphorylation, which was closely linked to chemoresistance [ 32 ]. Cai et al [ 33 ] found that Erk-mediated phosphorylation of Drp1 at residue S616 contributed to the mitochondrial fusion, a low mitochondrial ROS level, a high proglycolytic shift and drug resistance of T-cell acute lymphoblastic leukemia cells, treated with mesenchymal stem cells. Dong et al [ 34 ] found that Derlin-1 overexpression mediated chemoresistance of bladder cancer through PI3K/Akt and Erk/MMP signaling.…”