Protects Cancer Cells Research Articles

Skin cells protection against UVA radiation – the comparison of various antioxidants and viability tests

This study compares the effects of vitamins – including ascorbic acid, its derivative 3-O-ethyl-ascorbic acid (EAA), and tocopherol - as well as the main non-psychoactive phytocannabinoids on the viability of various skin cells, including healthy (keratinocytes/melanocytes/fibroblasts) and cancer cells (melanoma/SCC), under standard culture conditions and after the exposure to UVA radiation. All the conducted tests (MTT, SRB, and LDH) consistently indicate that the regenerative effect of EAA is stronger than that of ascorbic acid, while tocopherol acts selectively on healthy/cancer cells, inducing or inhibiting their proliferation, respectively. In the case of phytocannabinoids, only cannabidiol shows protective/regenerative properties for healthy cells. Moreover, the response of melanocytes to cannabigerol is divergent; however, only the LDH test indicates that cannabigerol strongly increases the membrane permeability of those cells. In summary it should be emphasized that various tests may give partially divergent results due to a variety of measured parameters. Nevertheless, despite the positive viability test results for the potential protective compound, caution should be taken as it may promote healthy skin cells but also protect cancer cells.

Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.

Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy.

CD47 predominates over CD24 as a macrophage immune checkpoint in cancer.

Macrophages hold tremendous promise as effectors of cancer immunotherapy, but the best strategies to provoke these cells to attack tumors remain unknown. Here, we evaluated the therapeutic potential of targeting two distinct macrophage immune checkpoints: CD47 and CD24. We found that antibodies targeting these antigens could elicit maximal levels of phagocytosis when combined together in vitro. However, to our surprise, via unbiased genome-wide CRISPR screens, we found that CD24 primarily acts as a target of opsonization rather than an immune checkpoint. In a series of in vitro and in vivo genetic validation studies, we found that CD24 was neither necessary nor sufficient to protect cancer cells from macrophage phagocytosis in most mouse and human tumor models. Instead, anti-CD24 antibodies exhibit robust Fc-dependent activity, and as a consequence, they cause significant on-target hematologic toxicity in mice. To overcome these challenges and leverage our findings for therapeutic purposes, we engineered a collection of 77 novel bispecific antibodies that bind to a tumor antigen with one arm and engage macrophages with the second arm. We discovered multiple novel bispecifics that maximally activate macrophage-mediated cytotoxicity and reduce binding to healthy blood cells, including bispecifics targeting macrophage immune checkpoint molecules in combination with EGFR, TROP2, and CD71. Overall, our findings indicate that CD47 predominates over CD24 as a macrophage immune checkpoint in cancer, and that the novel bispecifics we created may be optimal immunotherapies to direct myeloid cells to eradicate solid tumors.

NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination

The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC.

AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis.

Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.

Neutrophil extracellular traps promote tumor chemoresistance to anthracyclines.

The microenvironment plays an important role in promoting tumor cell chemoresistance, but the mechanisms responsible for this effect are not clear. Here, using models of multiple myeloma (MM) and solid cancers, we demonstrate a novel mechanism mediated by neutrophils, a major cell population in the bone marrow (BM), that protects cancer cells from chemotherapeutics. We show that in response to tumor-derived soluble factors, BM neutrophils release their DNA in the form of neutrophil extracellular traps (NETs). Cell-free DNA derived from NETs is then taken up by tumor cells via endocytosis and localizes to the cytoplasm. We found that both NETs and cell-free DNA taken up by tumor cells can bind anthracyclines, leading to tumor cell resistance to this class of chemotherapeutic agents. Targeting cell-free DNA with Pulmozyme or blocking NET formation with a PAD4 inhibitor abrogates the chemoprotective effect of neutrophils and restores sensitivity of tumor cells to anthracyclines.

Deciphering CD59: Unveiling Its Role in Immune Microenvironment and Prognostic Significance.

CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. The role of CD59 in cancer growth and interactions between CD59 and immune cells that modulate immune evasion has not been well explored. Using cancer patient database from The Cancer Genome Atlas (TCGA) and other public databases, we analyzed CD59 expression, its prognostic significance, and its association with immune cell infiltration in the tumor microenvironment, identifying associated genomic and functional networks and validating findings with invitro cell-line experimental data. This article describes the abundant expression of CD59 in multiple tumors such as cervical squamous cell carcinoma (CESC), kidney renal cell carcinoma (KIRC), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), and stomach adenocarcinoma (STAD), as well as in pan-cancer, using The Cancer Genome Atlas (TCGA) database and confirmed using multiple cancer cell lines. The expression of CD59 significantly alters the overall survival (OS) of patients with multiple malignancies such as CESC, GBM, HNSC, and STAD. Further, the correlation between CD59 and Treg and/or MDSC in the tumor microenvironment (TME) has shown to be strongly associated with poor outcomes in CESC, GBM, HNSC, and STAD as these tumors express high FOXP3 compared to KIRC. Moreover, unfavorable outcomes were strongly associated with the expression of CD59 and M2 tumor-associated macrophage infiltration in the TME via the IL10/pSTAT3 pathway in CESC and GBM but not in KIRC. In addition, TGFβ1-dominant cancers such as CESC, GBM, and HNSC showed a high correlation between CD59 and TGFβ1, leading to suppression of cytotoxic T cell activity. Overall, the correlation between CD59 and immune cells predicts its prognosis as unfavorable in CESC, GBM, HNSC, and STAD while being favorable in KIRC.

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

8817 IGF-II Regulates Magmas A Mitochondrial Protein Required For Cell Viability And ROS Protection

Abstract Disclosure: K. Granados: None. A. Durán: None. F. Almaguel: None. D. De Leon: None. Our laboratory previously showed that Insulin-like growth factor II (IGF-II) promotes cell proliferation, inhibits apoptosis and induces chemoresistance of Breast Cancer (BC) cells. We demonstrated that IGF-II achieves this by inhibiting pro-apoptotic proteins and stimulating anti-apoptotic proteins. Those studies also demonstrated that IGF-II prevented mitochondrial induced apoptosis by inhibiting depolarization of the mitochondrial membrane. Thus, IGF-II regulates the mitochondria to prevent cell death and to promote tumor growth and chemoresistance. Since IGF-II regulates mitochondrial proteins, we decided to assess how IGF-II regulates MAGMAS, a protein located in the inner mitochondrial membrane that is a critical component of a complex that controls mitochondrial protein import and ROS. Of note, MAGMAS was recently identified as being highly expressed in breast cancer, prostate cancer and during early fetal development which parallels IGF-II expression. Immunostaining of TNBC showed high levels of IGF-II and MAGMAS. Thus, our hypothesis is that IGF-II regulates MAGMAS and IGF-II secreting breast cancer cells will express higher levels of MAGMAS. Our preliminary results of rtPCR and Western blotting experiments validated our hypothesis demonstrating that IGF-II regulated the transcription of MAGMAS. To characterize the mechanisms by which IGF-II regulates MAGMAS, we chose the triple negative breast cancer (TNBC) cell line CRL-2335 which we demonstrated produces high levels of IGF-II and MAGMAS. CRL2335 cells were established from an AA TNBC patient and they express high levels of IGF-II and MAGMAS. Confocal microscopy and Western blotting and cellular fractionation were used to assess IGF-II regulation of MAGMAS in TNBC cells. The expression of MAGMAS was analyzed in wild CRL-2335, and IGF-II antisense transfected CRL-2335 cells and compared to cells treated with IGF-II. Results showed that CRL-2335 express high levels of MAGMAS in the mitochondria and blocking the expression of IGF-II by antisense technology significantly decreased MAGMAS. Exogenous IGF-II treatment to the antisense cells increased MAGMAS as demonstrated by Immunofluorescence and WB. Since IGF-II increases the localization of MAGMAS to the mitochondria we propose that IGF-II regulates MAGMAS to protect cancer cells from ROS induced cell death and chemoresistance. Completion of this study will validate IGF-II as a regulator of MAGMAS. Validation of IGF-II regulation of MAGMAS represents an important new tool for the treatment of TNBC. Presentation: 6/2/2024

Facilitating cholangiocarcinoma inhibition by targeting CD47

Immune evasion is one of the mechanisms by which cancer cells acquire immunity during cancer development and progression. One of these is the increased expression of cluster of differentiation 47 (CD47), a transmembrane glycoprotein that protects cells from phagocytic elimination. The interaction between CD47 and signal regulatory protein alpha (SIRPα) on macrophages alleviates the phagocytic signal. The present group previously reported high CD47 expression in cholangiocarcinoma (CCA), a major health problem in Thailand and East Asia, and that blocking CD47 using anti-CD47 antibodies promoted the removal of CCA. However, the mechanism through which CD47 inhibition attenuates CCA growth remains unclear. This study explored the clinical significance of targeting CD47 in CCA. Expression levels of CD47 and the macrophage marker CD68 were determined in CCA tissues by immunohistochemistry and correlated with clinical parameters. The role of CD47 in CCA cells was established using CD47-deficient KKU-213A CCA clones in vitro and in vivo. The results showed that CD47 was highly expressed in CCA tissues and significantly correlated with lymph node metastasis (P = 0.038). Moderate-to-dense CD68-positive infiltrating cells in CCA tissues were significantly associated with shorter survival of patients (P = 0.019) and were an independent prognostic factor of CCA patients as determined by the Cox proportional hazard model (hazard ratio, 2.040; 95 % confidence interval, 1.109–3.752; P = 0.022). Three CD47-deficient KKU-213A clones (#19, #23, and #28) were generated. The elimination of CD47 did not affect cell proliferation but increased monocyte-derived macrophage-mediated phagocytosis in vitro. Decreased tumor weights and volumes were observed in mice injected with CD47-deficient CCA clones. This revealed a significant role for CD47 in CCA, with a focus on protecting cancer cells from macrophage phagocytosis.

GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis.

Colorectal cancer (CRC) is a prevalent malignant tumor worldwide, leading to significant morbidity and disease burden. Diagnostic indicators and treatment objectives for CRC are urgently needed. This study demonstrates that GPR37, a GPCR receptor, is highly expressed in CRC. Depletion of GPR37 significantly reduced CRC tumor cell growth both in vitro and in vivo. Further tests showed that GPR37 protects cancer cells from ferroptosis by upregulating SCD1 expression, thereby modulating lipid metabolism, suppressing the level of reactive oxygen species, and mitigating ferroptosis. Mechanistic studies have shown that GPR37 modulates lipid metabolism in tumor cells by promoting SCD1 transcription via the MAPK-p38 signaling pathway. Our results reveal the pro-carcinogenic effect of GPR37 in primary CRC and suggest that targeting GPR37 could be a potential therapeutic target for CRC.

The BCL11A transcription factor stimulates the enzymatic activities of the OGG1 DNA glycosylase.

The BCL11A transcription factor has previously been shown to interact with and stimulate the enzymatic activities of the NTHL1 DNA glycosylase and Pol β polymerase. Here we show that BCL11A and a smaller peptide encompassing amino acids 160 to 520 can interact with the 8-oxoguanine DNA glycosylase, OGG1, increase the binding of OGG1 to DNA that contains an 8-oxoguanine base and stimulate the glycosylase activity of OGG1. Following BCL11A knockdown, we observed an increase in oxidized purines in the genome using comet assays, while immunoassays reveal an increase in 8-oxoG bases. Structure-function analysis indicates that the stimulation of OGG1 by BCL11A requires the zinc fingers 1, 2 and 3 as well as the proline-rich region between the first and second zing finger, but a glutamate-rich region downstream of zinc finger 3 is dispensable. Ectopic expression of a small peptide that contains the three zinc fingers can rescue the increase in 8-oxoguanine caused by BCL11A knockdown. These findings, together with previous results showing that BCL11A stimulates the enzymatic activities of NTHL1 and the Pol β polymerase, suggest that high expression of BCL11A is important to protect cancer cells against oxidative DNA damage.

Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor that functions in maintaining redox homeostasis in cells. It mediates the transcription of cytoprotective genes in response to environmental and endogenous stresses to prevent oxidative damage. Thus, Nrf2 plays a significant role in chemoprevention. However, aberrant activation of Nrf2 has been shown to protect cancer cells from apoptosis and contribute to their chemoresistance. The interaction between Nrf2 and CBP is critical for the gene transcription activation. CBP and its homologue p300 interact with two transactivation domains in Nrf2, Neh4, and Neh5 domains through their TAZ1 and TAZ2 domains. To date, the molecular basis of this crucial interaction is not known, hindering a more detailed understanding of the regulation of Nrf2. To close this knowledge gap, we have used a set of biophysical experiments to dissect the Nrf2-CBP/p300 interactions. Structural properties of Neh4 and Neh5 and their binding with the TAZ1 and TAZ2 domains of CBP/p300 were characterized. Our results show that the Neh4 and Neh5 domains of Nrf2 are intrinsically disordered, and they both can bind the TAZ1 and TAZ2 domains of CBP/p300 with micromolar affinities. The findings provide molecular insight into the regulation of Nrf2 by CBP/p300 through multi-domain interactions.

Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.Graphical

MYCN in neuroblastoma: The kings' new clothes and drugs

Deregulated levels of the MYCN oncogene contribute to the tumorigenesis of several human tumors including neuroblastoma. MYCN amplification classifies neuroendocrine tumors as high-risk and as a consequence is an unfavorable prognostic factor. MYCN has long been primarily described as a transcription factor, which binds to active promoters after heterodimerizing with MAX and directly regulates gene expression programs. New findings show that MYC proteins have novel oncogenic functions that are tumor-promoting and go beyond the regulation of gene expression. This review describes how MYCN continuously drives tumor progression by forming various protein complexes, for example to resolve torsional stress, coordinate transcription and replication, repair DNA damage and regulate R-loops. Interfering with the described processes as well as interfering with MYCN chromatin binding emerge as novel treatment strategies to indirectly target the oncoprotein. Furthermore, we describe the role of MYCN in metabolism and we review how these newly described functions of MYCN could be used as vulnerabilities for MYCN-driven tumors. Recent studies show that MYC proteins are capable of multimerizing at sites of genomic instability to protect cancer cells from stress. Additionally, MYCN can bind aberrant RNA transcripts, another feature to enhance the stress resilience of cancer cells, once again highlighting the oncogenic potential of MYC. Taken together, we show that the diverse functions of MYCN depend on its temporal and spatial dynamic interactome, making those interaction partners and functions crucial factors in the treatment of MYCN-related cancer.

FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer.

Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.

Procaine induces cell cycle arrest, apoptosis and autophagy through the inhibition of the PI3K/AKT and ERK pathways in human tongue squamous cell carcinoma.

Procaine (PCA), a local anesthetic commonly used in stomatology, exhibits antitumor activity in some human malignancies. However, the precise mechanism underlying PCA activity remains unknown, and its antitumor effect in human tongue squamous carcinoma cells has not been reported. Flow cytometry and western blotting were used to assess the effects of PCA on mitochondrial membrane potential (ΔΨm), intracellular reactive oxygen species (ROS) production, cell cycle and apoptosis. The results suggested that PCA inhibits CAL27 and SCC-15 cell proliferation, and clone formation in a dose-dependent manner. CAL27 cells were more sensitive to PCA than SCC-15 cells. PCA also significantly inhibited cell migration, induced mitochondrial damage, reduced ΔΨm and increased intracellular ROS production. PCA causes G2/M cycle arrest and induces apoptosis. The possible mechanism for the inhibition of human tongue squamous carcinoma cell proliferation is through the regulation of ERK phosphorylation and PI3K/AKT-mediated signaling pathways. The results further suggested that autophagy occurs during PCA-induced apoptosis in CAL27 cells, and the addition of the autophagy inhibitor hydroxychloroquine sulfate further enhanced the sensitivity of PCA to inhibit cell proliferation, indicating that autophagy plays an important role in protecting cancer cells from apoptosis. PCA shows potential as an anticancer drug and its combination with autophagy inhibitors enhances its sensitivity.

Bone Marrow Adipose Tissue.

Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT's impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma.

Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies.