Acetaminophen induces mitochondrial apoptosis through proteasome dysfunctions.

Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.

Role of Serotonergic System in Regulating Brain Tumor-Associated Neuroinflammatory Responses.

Serotonin signaling regulates wide arrays of both neural and extra-neural functions. Serotonin is also found to affect cancer progression directly as well as indirectly by modulating the immune cells. In the brain, serotonin plays a key role in regulating various functions; disturbance of the normal activities of serotonin leads to various mental illnesses, including the neuroinflammatory response in the central nervous system (CNS). The neuroinflammatory response can be initiated in various psychological illnesses and brain cancer. Serotonergic signaling can impact the functions of both glial as well as the immune cells. It can also affect the tumor immune microenvironment and the inflammatory response associated with brain cancers. Apart from this, many drugs used for treatment of psychological illness are known to modulate serotonergic system and can cross the blood-brain barrier. Understanding the role of serotonergic pathways in regulating neuroinflammatory response and brain cancer will provide a new paradigm in modulating the serotonergic components in treating brain cancer and associated inflammation-induced brain damages.

Effector and cytolytic function of natural killer cells in anticancer immunity.

Adaptive immune cells play an important role in mounting antigen-specific antitumor immunity. The contribution of innate immune cells such as monocytes, macrophages, natural killer (NK) cells, dendritic cells, and gamma-delta T cells is well studied in cancer immunology. NK cells are innate lymphoid cells that show effector and regulatory function in a contact-dependent and contact-independent manner. The cytotoxic function of NK cells plays an important role in killing the infected and transformed host cells and controlling infection and tumor growth. However, several studies have also ascribed the role of NK cells in inducing pathophysiology in autoimmune diseases, promoting immune tolerance in the uterus, and antitumor function in the tumor microenvironment. We discuss the fundamentals of NK cell biology, its distribution in different organs, cellular and molecular interactions, and its cytotoxic and noncytotoxic functions in cancer biology. We also highlight the use of NK cell-based adoptive cellular therapy in cancer.

Key Activating and Inhibitory Ligands Involved in the Mobilization of Natural Killer Cells for Cancer Immunotherapies.

Natural killer (NK) cells are the most potent arm of the innate immune system and play an important role in immunity, alloimmunity, autoimmunity, and cancer. NK cells recognize "altered-self" cells due to oncogenic transformation or stress due to viral infection and target to kill them. The effector functions of NK cells depend on the interaction of the activating and inhibitory receptors on their surface with their cognate ligand expressed on the target cells. These activating and inhibitory receptors interact with major histocompatibility complex I (MHC I) expressed on the target cells and make decisions to mount an immune response. NK cell immune response includes cytolytic activity and secretion of cytokines to help with the ongoing immune response. The advancement of our knowledge on the expression of inhibitory and activating molecules led us to exploit these molecules in the treatment of cancer. This review discusses the importance of activating and inhibitory receptors on NK cells and their clinical importance in cancer immunotherapy.

Role of serotonin receptor signaling in cancer cells and anti-tumor immunity.

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter known to affect emotion, behavior, and cognition, and its effects are mostly studied in neurological diseases. The crosstalk between the immune cells and the nervous system through serotonin and its receptors (5-HTRs) in the tumor microenvironment and the secondary lymphoid organs are known to affect cancer pathogenesis. However, the molecular mechanism of - alteration in the phenotype and function of - innate and adaptive immune cells by serotonin is not well explored. In this review, we discuss how serotonin and serotonin receptors modulate the phenotype and function of various immune cells, and how the 5-HT-5-HTR axis modulates antitumor immunity. Understanding how 5-HT and immune signaling are involved in tumor immunity could help improve therapeutic strategies to control cancer progression and metastasis.