Endoplasmic reticulum stress promoting caspase signaling pathway-dependent apoptosis contributes to bone cancer pain in the spinal dorsal horn

Abstract

Background: Management of bone cancer pain is difficult because of its complex mechanisms, which has a major impact on the quality of patients' daily life. Recent studies have indicated that endoplasmic reticulum stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to endoplasmic reticulum stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the endoplasmic reticulum stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-bearing rats and whether it thereby induces bone cancer pain. Methods: Bone cancer pain was measured behaviorally by the paw withdrawal threshold. The expression levels of endoplasmic reticulum stress markers, namely, immunoglobulin-binding protein/glucose-regulated protein 78 (BIP/GRP78), activating transcription factor-6 (ATF6), phosphorylated inositol-requiring enzyme-1 (p-IRE1), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) and cleaved caspase-3, were quantitatively assessed by western blot. The distribution of p-eIF2a (an endoplasmic reticulum marker) and cleaved caspase-3 in the lumbar enlargement of the spinal cord was determined by immunohistochemistry in spinal dorsal horn slices. Results: Bone cancer pain suffered bone damage and persistent mechanical allodynia. Bone cancer pain increased the expression of GRP78, ATF6, p-PERK, p-IRE1, and cleaved caspase-3 in a rat model of bone cancer pain. In addition, p-eIF2a and cleaved caspase-3 were localized to neurons. The intrathecal injection of tauroursodeoxycholic acid as a specific inhibitor of endoplasmic reticulum stress attenuated bone cancer pain and reduced the expression of GRP78, ATF6, p-PERK, p-IRE1, and cleaved caspase-3 in the spinal cord. Moreover, Z-DEVD-FMK (FMK) was also shown to attenuate bone cancer pain. Conclusion: Endoplasmic reticulum stress causes the activation of caspase signaling pathway-dependent apoptosis in neuronal cells and induces bone cancer pain-related hyperalgesia.

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons

“…The tumor cells were prepared according to a previously described protocol [ 32 – 34 ]. Walker 256 breast cancer cells were kindly provided by the Nanjing University of Chinese Medicine.…”

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

“…Intrathecal blockage of ER stress impairs caspase-3 cleavage-dependent apoptosis in dorsal horn neurons and relieves bone cancer pain. More importantly, spinal therapy with a specific caspase-3 inhibitor Z-DEVD-FMK is enough and effective against bone cancer pain ( He et al, 2019 ). Also, the modulation of Bax overload and caspase-3 cleavage in mitochondrial fission and apoptosis in bone cancer pain is confirmed by other research teams ( Li MY.…”

Apoptosis and (in) Pain—Potential Clinical Implications

“…The induction of apoptosis can be divided into three steps: the inducing agent’s interaction with the cell, the biochemical transduction of the death signal, and the execution by the apoptotic machinery. Different extracellular signals, such as an increase in ROS production [ 41 ] and/or a decrease in antioxidants resulting in oxidative stress, inflammatory mediators such as TNF- α and IL1-β [ 42 ], moderate hyperactivity stimulation of the N-methyl-D-aspartate (NMDA) receptors [ 1 ], and the endoplasmic reticulum stress [ 43 ] could activate signal transduction pathways that converge on a final common pathway leading to the execution phase of cellular apoptosis. At least two pathways are involved, the mitochondria-dependent pathway (intrinsic or mitochondrial pathway), which is mediated by mitochondria and the B-cell lymphoma-2 (BCL-2) family proteins, and the extrinsic or membrane pathway involving external signaling via membrane receptors from the tumor necrosis factor (TNF) family, such as TNF-R1, FAS, TNF-apoptotic inducing ligand receptors 1 and 2 (TRAIL-R1 and 2, or death receptors DR4 and 5 [ 44 ], and the low-affinity nerve growth factor (NGF) receptor, p75-NTR [ 27 , 45 ].…”

“…As a result, IκBα releases the p65/p50 complex, which subsequently translocates to the nucleus and initiates the transcription of several genes, including inflammatory genes such as TNFα, IL-1β, and cyclooxogenase-2 (COX-2) that directly or indirectly influence pain [ 64 , 65 , 66 ]. Thus, targeting the NF-kB pathway, namely by inhibiting the IkB degradation in the UPP could be a new therapeutic approach to treating pain [ 43 , 64 , 65 ].…”

“…The accumulation of unfolded proteins in the ER can activate the UPR to restore ER function. Besides the increase in ER stress as a self-protective signal transcription pathway after mild injury, the failure of this system to relieve prolonged or excessive ER stress may cause cell apoptosis, and plays an important role in neuropathic pain, specifically in rat models of bone cancer pain [ 43 ].…”