Abstract
Multiple myeloma (MM) is a B-cell malignancy requiring inflammatory microenvironment signals for cell survival and proliferation. Despite improvements in pharmacological tools, MM remains incurable mainly because of drug resistance. The present study aimed to investigate the implication of Toll-like receptor 4 (TLR4) as the potential mechanism of bortezomib (BTZ) resistance. We found that TLR4 activation induced mitochondrial biogenesis and increased mitochondrial mass in human MM cell lines. Moreover, TLR4 signaling was activated after BTZ exposure and was increased in BTZ-resistant U266 (U266-R) cells. A combination of BTZ with TAK-242, a selective TLR4 inhibitor, overcame drug resistance through the generation of higher and extended oxidative stress, strong mitochondrial depolarization and severe impairment of mitochondrial fitness which in turn caused cell energy crisis and activated mitophagy and apoptosis. We further confirmed the efficacy of a TAK-242/BTZ combination in plasma cells from refractory myeloma patients. Consistently, inhibition of TLR4 increased BTZ-induced mitochondrial depolarization, restoring pharmacological response. Taken together, these findings indicate that TLR4 signaling acts as a stress-responsive mechanism protecting mitochondria during BTZ exposure, sustaining mitochondrial metabolism and promoting drug resistance. Inhibition of TLR4 could be therefore be a possible target in patients with refractory MM to overcome BTZ resistance.
Highlights
Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells in the bone marrow (BM)
Toll-like receptor 4 (TLR4) maymay be involved in the in mitochondria biogenesis of humanof myeloma
The mitochondrial membrane promoting potential and release ofofcytochrome oxygen species (ROS), alteration in the mitochondrial membrane potential and release of cytochrome c [29], we hypothesized that MM cells may activate TLR4 signalling during exposure to BTZ as a c [29], we hypothesized that MM cells may activate TLR4 signalling during exposure to BTZ as a stress-responsive mechanism to protect mitochondria against drug-induced apoptosis
Summary
Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells in the bone marrow (BM). Several mechanisms are suggested to be responsible for disease progression and Toll-like receptors (TLRs) seem to play an important role with particular regard to the microenvironment molecular mechanisms, TLRs are potential linking elements between inflammation and cancer [2]. We recently demonstrated that TLR4 signalling plays a key role in mesenchymal stromal cells (MSC) transformation by inducing a proinflammatory phenotype associated with a protumor behaviour, allowing immune escape mechanisms and tumor growth in the myeloma microenvironment [17]. MM cells’on mitochondrial dynamics and energy and energy metabolism as the potentially active mechanism of drug resistance to BTZ.
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