• PDZ-binding kinase
• glutathione
• medulloblastoma
• rabies virus glycoprotein
• tumor microenvironment-responsive nanocomposite

• Humans
• Medulloblastoma/pathology
• Medulloblastoma/drug therapy
• Medulloblastoma/genetics
• Medulloblastoma/therapy
• Cell Line, Tumor
• Tumor Microenvironment/drug effects
• RNA, Small Interfering/genetics
• Nanoparticles/chemistry
• Nanoparticles/administration & dosage
• Apoptosis/drug effects
• Cell Proliferation/drug effects
• Nanoparticle Drug Delivery System/chemistry
• Polyamines

• acetylcholine
• brain–gut axis
• cancer
• cellular signaling
• gastrointestinal cancer
• muscarinic receptors
• nicotinic receptors
• protein kinases

• Humans
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/pathology
• Acetylcholine/metabolism
• Animals
• Signal Transduction
• Receptors, Muscarinic/metabolism
• Receptors, Nicotinic/metabolism

Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.

• K+ channel
• actin
• alzheimer’s disease
• apoptosis
• cancer
• traumatic brain injury

Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.

To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.

Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.

Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.

Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.

• Breast cancer
• Paclitaxel
• Nicotinic acetylcholine receptors
• Drug therapy
• Signal transduction
• Drug transporter

• Chongqing Science and Technology Commission