African American men face a stark prostate cancer (PCa)-related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome-based "protein signature" for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2-fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry-based proteomic analysis of serum exosomes identified seven unique and fifty-five overlapping proteins (up- or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute-phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA-hT cells secreted exosomes strongly induced a proinflammatory M2-phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6-fold) in exosomes from African Americans with PCa, but a lesser loading (0.6-fold) was observed in exosomes from Caucasian men with PCa compared to race-matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1885

Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients.

The actin cytoskeleton plays a crucial role in many cellular processes while its reorganization is important in maintaining cell homeostasis. However, in the case of cancer cells, actin and ABPs (actin-binding proteins) are involved in all stages of carcinogenesis. Literature has reported that ABPs such as SATB1 (special AT-rich binding protein 1), WASP (Wiskott-Aldrich syndrome protein), nesprin, and villin take part in the initial step of carcinogenesis by regulating oncogene expression. Additionally, changes in actin localization promote cell proliferation by inhibiting apoptosis (SATB1). In turn, migration and invasion of cancer cells are based on the formation of actin-rich protrusions (Arp2/3 complex, filamin A, fascin, α-actinin, and cofilin). Importantly, more and more scientists suggest that microfilaments together with the associated proteins mediate tumor vascularization. Hence, the presented article aims to summarize literature reports in the context of the potential role of actin and ABPs in all steps of carcinogenesis.

Involvement of Actin and Actin-Binding Proteins in Carcinogenesis

Filamin A (FlnA) is a well-known actin cross-linking protein. It serves as a scaffold for over 90 binding partners and involves in multiple cell functions, of which cell migration and adhesion is especially critical. Recently, its role in the cell has come under scrutiny for FlnA's involvement in cancer development. Originally revealed as a cancer-promoting protein, FlnA actually plays a dual role in cancers. When localized to the cytoplasm, FlnA has a tumor-promoting effect by interacting with signaling molecules. While once localized to the nucleus, it may act to suppress tumor growth and inhibit metastasis by interacting with transcription factors. Thus drugs that can cause FlnA to transpose from cytoplasm to nucleus could be a promising treatment for cancers. Study to this end is on the way in prostate cancer and the results are encouraging. FlnA has been studied in large categories of cancers, such as prostate cancer, breast cancer, melanoma, lung cancer, etc. However, most studies did not evaluate the differences that arise from the localization of the protein, which was a great pity! What's more, although FlnA's is undoubtedly important in cancer invasion and metastasis, both preclinical and clinical researches are very rare in some highly metastatic cancers, such as pancreatic cancer. In this mini-review, we give a comprehensive summary of FlnA' s expression in cancers. Where available, we also indicate the correlation of FlnA with cancer stages and patient prognosis, and clarify its localization (nucleus/cytoplasm) and its dual role (promote/suppress) in different cancers.

Filamin A: Insights into its Exact Role in Cancers.

The small GTPase Rac1 has been implicated in a variety of dynamic cell biological processes, including cell proliferation, cell survival, cell-cell contacts, epithelial mesenchymal transition (EMT), cell motility, and invasiveness. These processes are orchestrated through the fine tuning of Rac1 activity by upstream cell surface receptors and effectors that regulate the cycling Rac1-GDP (off state)/Rac1-GTP (on state), but also through the tuning of Rac1 accumulation, activity, and subcellular localization by post translational modifications or recruitment into molecular scaffolds. Another level of regulation involves Rac1 transcripts stability and splicing. Downstream, Rac1 initiates a series of signaling networks, including regulatory complex of actin cytoskeleton remodeling, activation of protein kinases (PAKs, MAPKs) and transcription factors (NFkB, Wnt/β-catenin/TCF, STAT3, Snail), production of reactive oxygen species (NADPH oxidase holoenzymes, mitochondrial ROS). Thus, this GTPase, its regulators, and effector systems might be involved at different steps of the neoplastic progression from dysplasia to the metastatic cascade. After briefly placing Rac1 and its effector systems in the more general context of intestinal homeostasis and in wound healing after intestinal injury, the present review mainly focuses on the several levels of Rac1 signaling pathway dysregulation in colorectal carcinogenesis, their biological significance, and their clinical impact.

https://www.mdpi.com/2072-6694/12/3/665/pdf

Rac1 Signaling: From Intestinal Homeostasis to Colorectal Cancer Metastasis.

Palmitic acid (PA) is a saturated fatty acid commonly found in coconut oil and palm oil. It serves as an energy source for the body and plays a role in the structure and function of cell membranes. Beyond its industrial applications, PA has gained attention for its potential therapeutic properties. Modern pharmacological studies have demonstrated that PA exhibits anti-inflammatory, antioxidant, and immune-enhancing effects. In recent years, PA has emerged as a promising anti-tumor agent with demonstrated efficacy against various malignancies including gastric cancer, liver cancer, cervical cancer, breast cancer, and colorectal cancer. Its anti-tumor effects encompass inducing apoptosis in tumor cells, inhibiting tumor cell proliferation, suppressing metastasis and invasion, enhancing sensitivity to chemotherapy, and improving immune function. The main anticancer mechanism of palmitic acid (PA) involves the induction of cell apoptosis through the mitochondrial pathway, facilitated by the promotion of intracellular reactive oxygen species (ROS) generation. PA also exhibits interference with the cancer cell cycle, leading to cell cycle arrest predominantly in the G1 phase. Moreover, PA induces programmed cell autophagy death, inhibits cell migration, invasion, and angiogenesis, and synergistically enhances the efficacy of chemotherapy drugs while reducing adverse reactions. PA acts on various intracellular and extracellular targets, modulating tumor cell signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), endoplasmic reticulum (ER), B Cell Lymphoma-2 (Bcl-2), P53, and other signaling pathways. Furthermore, derivatives of PA play a significant regulatory role in tumor resistance processes. This paper provides a comprehensive review of recent studies investigating the anti-tumor effects of PA. It summarizes the underlying mechanisms through which PA exerts its anti-tumor effects, aiming to inspire new perspectives for the treatment of malignant tumors in clinical settings and the development of novel anti-cancer drugs. 

Molecular mechanism of palmitic acid and its derivatives in tumor progression

Abstract Context Paclitaxel (PTX) leads to chemotherapy brain (chemo-brain) which is characterised by cognitive impairment. It has been reported that necroptosis is associated with cognitive impairment in some neurodegenerative diseases, but it is not clear whether it is related to the development of chemo-brain. Objective To investigate the role of necroptosis and related changes in PTX-induced cognitive impairment. Materials and methods C57bl/6n mice were randomly divided into five groups: control, vehicle, and different concentrations of PTX (6, 8, 10 mg/kg). Two additional groups received pre-treatment with Gdcl3 or PBS through Intracerebroventricular (ICV) injection before PTX-treatment. Cognitive function, necroptosis, synaptic plasticity and microglia polarisation were analysed. Results PTX (10 mg/kg) induced significant cognitive impairment, accompanied by changes in synaptic plasticity, including decreased density of PSD95 (0.65-fold), BDNF (0.44-fold) and dendritic spines (0.57-fold). PTX induced necroptosis of 53.41% (RIP3) and 61.91% (MLKL) in hippocampal neurons, with high expression of RIP3 (1.58-fold) compared with the control group. MLKL (1.87-fold) exhibited the same trend, reaching a peak on the 14th day. The increased expression of iNOS (1.63-fold) and inflammatory factors such as TNF-α (1.85-fold) and IL-β (1.89-fold) compared to the control group suggests that M1 polarisation of microglia is involved in the process of cognitive impairment. Pre-treatment with Gdcl3 effectively reduced the number of microglia (0.50-fold), inhibited the release of TNF-α (0.73-fold) and IL-β (0.56-fold), and improved cognitive impairment. Conclusion We established a stable animal model of PTX-induced cognitive impairment and explored the underlying pathophysiological mechanism. These findings can guide the future treatment of chemo-brain.

https://www.tandfonline.com/doi/pdf/10.1080/13880209.2022.2108064?needAccess=true

Paclitaxel induces cognitive impairment via necroptosis, decreased synaptic plasticity and M1 polarisation of microglia

AIM: To determine the expression and significance of filamin A (FLNa) in colorectal adenocarcinoma tissue.

METHODS: The expression of FLNa in 46 colorectal cancer tissues and normal tissues was detected by immunohistochemistry, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, and its relationship with clinical parameters and prognosis was analyzed.

RESULTS: The positive expression of FLNa in cancer tissues was lower than that in normal mucosa, and the difference was statistically significant. The expression of FLNa correlated with liver metastasis, lymph node metastasis and rectal invasion depth, regardless of sex, age, tumor location, tumor size, gross shape and histological type of colorectal carcinoma. Multivariate analysis showed that FLNa was an independent risk factor for postoperative survival of patients with colorectal adenocarcinoma. Moreover, survival analysis showed that the expression level of FLNa was closely related with survival of patients with colorectal adenocarcinoma. The results of RT-PCR and Western blotting were consistent with those of immunohistochemistry.

CONCLUSION: FLNa showed low expression in colorectal adenocarcinoma, high correlation with the incidence and development of colorectal cancer, and was considered an indicator of prognosis.

New cancer suppressor gene for colorectal adenocarcinoma: filamin A.

Paclitaxel-treated patients frequently experience chemotherapy-induced peripheral neuropathy (CIPN) and mood changes, such as anxiety. Layer II/III of the medial prefrontal cortex (mPFC) is vital for generating pain and emotions. However, it is unclear whether glutamatergic neurons in layer II/III of the mPFC are involved in regulating paclitaxel-induced neuropathic pain and anxiety. Here, we determined the role of glutamatergic neurons in layer II/III of the mPFC in paclitaxel (4 mg/kg/d, consecutive 8 days, intraperitoneal injection, cumulative dose: 32 mg/kg)-induced pain and anxiety by using a combination of behavior testing's, immunostaining, chemogenetics, optogenetics, fiberphotometry, and morphological approaches. The number of c-Fos-positive neurons expressing calcium/calmodulin-dependent protein kinase II (CaMKII) (CaMKII-positive neurons) were increased in layer II/III of the mPFC in paclitaxel-treated mice. Selectively inhibiting CaMKII-positive neurons in layer II/III of the mPFC with chemogenetic or optogenetic approaches relieved paclitaxel-induced neuropathic pain and anxiety. Furthermore, paclitaxel treatment increased calcium signals in layer II/III of the mPFC CaMKII-positive neurons expressed GCaMP6m. In addition, Golgi staining was performed to analyze that basal and apical dendrites of pyramidal neurons in layer II/III of the mPFC. Compared with vehicle-treated mice, paclitaxel-treated mice displayed longer and more branches and increased spine density in layer II/III of the mPFC. Further electron microscopy analysis revealed that asymmetrical synapses and postsynaptic density 95 thickness were significantly increased in layer II/III of the mPFC in paclitaxel-treated mice. These data suggest that CaMKII neurons in the mPFC layer II/III are importantly involved in paclitaxel-induced pain and anxiety. 

Inhibition of glutamatergic neurons in layer II/III of the medial prefrontal cortex alleviates paclitaxel-induced neuropathic pain and anxiety.

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Paclitaxel induces cognitive impairment via necroptosis, decreased synaptic plasticity and M1 polarisation of microglia

New cancer suppressor gene for colorectal adenocarcinoma: filamin A.

Inhibition of glutamatergic neurons in layer II/III of the medial prefrontal cortex alleviates paclitaxel-induced neuropathic pain and anxiety.