An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer

Robinson, T.; Osman, Mahasin A.

doi:10.3390/cancers15133464

Cited by 3 publications

(1 citation statement)

References 99 publications

(106 reference statements)

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“…These findings highlight the potential role of S1R in these diseases. Several studies have demonstrated a tumor-promoting role for S1R [59,60]. If S1R protects cells from ferroptosis, the tumor-promoting effect of this receptor makes sense.…”

Section: Protection Against Ferroptosis By S1r and Its Relationship T...mentioning

confidence: 99%

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Nguyen,

Jaramillo-Martinez,

Mathew

et al. 2023

IJMS

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Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein–protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.

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Section: Protection Against Ferroptosis By S1r and Its Relationship T...mentioning

confidence: 99%

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Nguyen,

Jaramillo-Martinez,

Mathew

et al. 2023

IJMS

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Sigma-1 receptor targeting inhibits connexin 43 based intercellular communication in chronic neuropathic pain

Denaro,

D’Aprile,

Torrisi

et al. 2024

Inflamm. Res.

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Background and objective Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain. Methods A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084. Results (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction (GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain. Conclusions This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention.

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Role of Scaffold Proteins in the Heterogeneity of Glioblastoma

Iyer,

Donahue,

Osman

2024

Preprint

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Glioblastoma (GB) is a highly heterogeneous type of incurable brain cancer with a low survival rate. Intensive ongoing research has identified several potential targets; however, GB is marred by the activation of multiple pathways, and thus common targets are highly sought after. The signal regulatory scaffold IQGAP1 is an oncoprotein implicated in GB. IQGAP1 nucleates a myriad of pathways in a contextual manner and modulates many of the targets altered in GB like MAPK, NF-κB, and mTOR/PI3K/Akt1, thus positioning it as a plausible common therapeutic target. Here, we review the targets that are subjects of GB treatment clinical trials and the commonly used animal models that facilitate target identification. We propose a model in which the dysfunction of various IQGAP1 pathways can explain to a larger extent some of the GB heterogeneity and offer a platform for personalized medicine.

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An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer

Cited by 3 publications

References 99 publications

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Sigma-1 receptor targeting inhibits connexin 43 based intercellular communication in chronic neuropathic pain

Role of Scaffold Proteins in the Heterogeneity of Glioblastoma

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