Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma

Hasegawa, Kazuaki; Okui, Tatsuo; Shimo, Tsuyoshi; Ibaragi, Soichiro; Kawai, Hiroki; Ryumon, Shoji; Kishimoto, Kenji; Okusha, Yuka; Hassan, Nur Mohammad Monsur; Sasaki, Akira

doi:10.3390/ijms19113317

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…The 4T1 BC cells (1 × 10 5 cells/10 μl) were inoculated in the bone marrow cavity of right tibiae of 4 to 6-week-old female BALB/c mice (4T1 mice) (Harlan Laboratories, Indianapolis, IN), under general anesthesia with ketamine (Ketaset; 90–150 mg/kg, ip) and xylazine (AnaSed; 5–10 mg/kg, ip) as we described [21] . Sham surgery control mice were injected intratibially with PBS.…”

Section: Methods Smentioning

confidence: 99%

The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone

Okui

Hiasa

Ryumon

et al. 2021

Journal of Bone Oncology

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Section: Methods Smentioning

confidence: 99%

The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone

Okui

Hiasa

Ryumon

et al. 2021

Journal of Bone Oncology

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“…The results of this study and previous studies indicate that MCTs transfer lactate from astrocytes to neurons that are involved in the initiation and sustained of inflammatory and neuropathic pain. Furthermore, another study indicated that head and neck squamous cell carcinoma induces an acidic bone microenvironment and leads to bone pain via the lactate transporter MCT 4 42. Thus, the collected evidence reveals that MCTs are involved in pathological processes in some pain states, and it also supports the astrocyte–neurone lactate shuttle hypothesis of pain mechanisms.…”

Section: Discussionmentioning

confidence: 55%

<p>Inhibition Of Monocarboxylate Transporter 1 In Spinal Cord Horn Significantly Reverses Chronic Inflammatory Pain</p>

Wang

et al. 2019

JPR

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PurposeChronic inflammatory pain is a common condition in the clinic, and the underlying mechanism is not being completely understood. Various studies have demonstrated that central and peripheral sensitization and synaptic plasticity could play crucial functions in chronic inflammatory pain. Moreover, families of monocarboxylate transporters (MCTs) are closely related to cellular metabolism and synaptic plasticity, and it is also reported that MCTs participate in chronic inflammatory pain. Nevertheless, there is a probability of the engaging role of MCT 1 is in chronic inflammatory pain, but its specific cellular level mechanism is yet to be investigated. In our study, we hypothesized that MCT 1 in the spinal dorsal horn plays an important part in chronic inflammatory pain.MethodsIn experiment A, rats were gone through nociceptive behavioral testing at 1 d day before and 1 d, 3 d, and 7 d after completing complete Freund’s adjuvant (CFA) injection. The specimens collected for detecting MCT 1 by Western blotting. In experiment B, rats were randomly divided into four groups. Intrathecal injection of MCT 1 inhibitor and nociceptive behavioral tests were performed 1 d day before and 1 d, 3 d, 7 d, 14 d, and 21 d after CFA injection. MCT 1 and p-ERK levels in spinal dorsal horn were measured by Western blotting, and GFAP in spinal dorsal horn was detected by immunofluorescence.ResultsThe expression of MCT 1 in the spinal dorsal horn was increased during chronic inflammatory pain in rats. The intrathecal injection of an MCT 1 inhibitor evidently diminished the expression of MCT 1 and GFAP in the spinal dorsal horn, and the behavioral nociceptive responses were also attenuated. Meanwhile, the expression of p-ERK was also decreased by the intrathecal injection of an MCT 1 inhibitor.ConclusionOur results indicate that MCT 1 very likely play a critical role in regulating chronic inflammatory pain and may influence the regulation of synaptic plasticity via ERK in the spinal dorsal horn of rats.

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“…Cancer cells produce large amounts of lactate resulting from the Warburg effect ( 28 ) and actively secrete it via the lactate transporter MCT4 ( 13 ) to avoid cell death due to intracellular lactate acidosis. Secreted lactate is then taken up by neighboring cells, such as stromal, endothelial and immune cells, in the tumor microenvironment via the lactate transporter MCT1 as an energy source ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81

et al. 2023

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Breast cancer (BC) bone metastasis causes bone pain (BP), which detrimentally damages the quality of life and outcome of patients with BC. However, the mechanism of BC-BP is poorly understood, and effective treatments are limited. The present study demonstrated a novel mechanism of BC-BP using a mouse model of bone pain, in which mouse (EO771) and human (MDA-MB-231) BC cells were injected in the bone marrow cavity of tibiae. Western blot analysis using sensory nerves, in vivo assessment of cancer pain and in vitro calcium flux analysis were performed. These mice developed progressive BC-BP in tibiae in conjunction with an upregulation of phosphorylated pERK1/2 and cAMP-response element-binding protein (pCREB), which are molecular indicators of neuron excitation, in the dorsal root ganglia (DRG) of sensory nerves. Importantly, mice injected with BC cells, in which the expression of the lactic acid transporter monocarboxylate transporter 4 (MCT4) was silenced, exhibited decreased BC-BP with downregulated expression of pERK1/2 and pCREB in the DRG and reduced circulating levels of lactate compared with mice injected with parental BC cells. Further, silencing of the cell-surface orphan receptor for lactate, G protein-coupled receptor 81 (GPR81), in the F11 sensory neuron cells decreased lactate-promoted upregulation of pERK1/2 and Ca 2+ influx, suggesting that the sensory neuron excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC-BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC-BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC-BP.

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Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma

Cited by 6 publications

References 26 publications

The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone

The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone

<p>Inhibition Of Monocarboxylate Transporter 1 In Spinal Cord Horn Significantly Reverses Chronic Inflammatory Pain</p>

Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81

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