Cell death shapes cancer immunity: spotlighting PANoptosis.

PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis. PANoptosis is governed by a newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each of these PCD types individually, PANoptosis is still in the early stages of research and warrants further exploration of its specific regulatory mechanisms and primary targets. In this review, we provide a brief overview of the conceptual framework and molecular components of PANoptosis. In addition, we highlight recent advances in the understanding of the molecular mechanisms and therapeutic applications of PANoptosis. By elucidating the complex crosstalk between pyroptosis, apoptosis and necroptosis and summarizing the functional consequences of PANoptosis with a special focus on the tumor immune microenvironment, this review aims to provide a theoretical basis for the potential application of PANoptosis in cancer therapy.

Cancer metabolism and carcinogenesis.

Metabolic reprogramming is an emerging hallmark of cancer cells, enabling them to meet increased nutrient and energy demands while withstanding the challenging microenvironment. Cancer cells can switch their metabolic pathways, allowing them to adapt to different microenvironments and therapeutic interventions. This refers to metabolic heterogeneity, in which different cell populations use different metabolic pathways to sustain their survival and proliferation and impact their response to conventional cancer therapies. Thus, targeting cancer metabolic heterogeneity represents an innovative therapeutic avenue with the potential to overcome treatment resistance and improve therapeutic outcomes. This review discusses the metabolic patterns of different cancer cell populations and developmental stages, summarizes the molecular mechanisms involved in the intricate interactions within cancer metabolism, and highlights the clinical potential of targeting metabolic vulnerabilities as a promising therapeutic regimen. We aim to unravel the complex of metabolic characteristics and develop personalized treatment approaches to address distinct metabolic traits, ultimately enhancing patient outcomes.

Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer.

Radiotherapy plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSCC), yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. Here we report that radioresistant HNSCC cells exhibit increased tumor aggressiveness. Using unbiased proteome profiler antibody arrays, we identify that upregulation of c-Met phosphorylation is one of the critical mechanisms for radioresistance in HNSCC cells. We further uncover that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but is suppressed by its genetic knockdown and pharmacologic inactivation. Mechanistically, the resulting upregulation of c-Met promotes elevated expression of plexin domain containing 2 (PLXDC2) through activating ERK1/2-ELK1 signaling, which in turn modulates cancer cell plasticity by epithelial-mesenchymal transition (EMT) induction and enrichment of the cancer stem cell (CSC) subpopulation, leading to resistance of HNSCC cells to radiotherapy. Depletion of PLXDC2 overcomes c-Met-mediated radioresistance through reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, the addition of SU11274, a selective and potent c-Met inhibitor, to radiation induces tumor shrinkage and limits tumor metastasis to lymph nodes in an orthotopic mouse model. Collectively, these significant findings not only demonstrate a novel mechanism underpinning radioresistance-associated aggressiveness but also provide a possible therapeutic strategy to target radioresistance in patients with HNSCC. Significance: This work provides novel insights into c-Met-PLXDC2 signaling in radioresistance-associated aggressiveness and suggests a new mechanism-informed therapeutic strategy to overcome failure of radiotherapy in patients with HNSCC.

Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States.

BACKGROUND: Immune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients. METHODS: irAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software. RESULTS: irAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. 'Respiratory, thoracic and mediastinal disorders' and 'gastrointestinal disorders' were the two most common groups of disorders caused by the seven ICIs studied. 'Cardiac disorders' was the main type of disorders caused by these ICIs in cancer patients aged 65-85, while 'reproductive system and breast disease' was the main type of disorder in cancer patients aged 18-64. 'Respiratory, thoracic, mediastinal diseases' and 'reproductive system and breast diseases' were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively. CONCLUSION: Tissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.

BACKGROUND: Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined. METHODS: We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice. RESULTS: ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment. CONCLUSIONS: These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.

The New Frontier of Three-Dimensional Culture Models to Scale-Up Cancer Research.

In vitro cancer research models require the utmost accuracy and precision to effectively investigate physiological pathways and mechanisms, as well as test the therapeutic efficacy of anticancer drugs. Although two-dimensional (2D) cell culture models have been the traditional hallmark of cancer research, increasing evidence suggests 2D tumor models cannot accurately recapitulate complex aspects of tumor cells and drug responses. Three-dimensional (3D) cell cultures, however, are more physiologically relevant in oncology as they model the cancer network and microenvironment better, allowing for development and assessment of natural products and other anticancer drugs. The present review outlines unprecedented ways in which multicellular spheroid models, organoid models, hydrogel models, microfluidic devices, microfiber scaffold models, and tissue-engineered scaffold models are used in this research. The future of cancer research lies within 3D cell cultures, and as this approach improves, cancer research will continue to advance.

PGK1 : An Essential Player in Modulating Tumor Metabolism.

Phosphoglycerate kinase 1 (PGK1) is the first enzyme in glycolysis to generate a molecule of ATP in the conversion of 1,3-bisphosphoglycerate (1,3-BPG) to 3-phosphoglycerate (3-PG). In addition to the role of glycolysis, PGK-1 acts as a polymerase alpha cofactor protein, with effects on the tricarboxylic acid cycle, DNA replication and repair. Posttranslational modifications such as methylation, phosphorylation, and acetylation have been seen to activate PGK1 in cancer. High levels of intracellular PGK1 are associated with tumorigenesis and progression, and chemoradiotherapy resistance. However, high levels of extracellular PGK1 suppress angiogenesis and subsequently counteract cancer malignancy. Here we have summarized the current knowledge on the mechanisms and effects of PGK1 in various tumor types and evaluated its potential prognostic and therapeutic value in cancer. The data summarized here aims at providing molecular information and new ideas of employing natural products to combat cancer associated with PGK1.

Evaluating the Anticancer Activity of Natural Products Using a Novel 3D Culture Model.

Natural products, particularly as anticancer agents, continue to provide prototypes for pharmacologically active compounds. Compared with traditional two-dimensional (2D) approaches, 3D cell cultures have shown a clear role in drug discovery and development as they more closely resemble in vivo cell environments and come closer to capturing the in vivo functions of organs and tissues. The growing interest in using more physiological in vitro cancer models has driven the adoption of 3D cell cultures in evaluating anticancer activities of natural products. Here, we establish a protocol to use a novel 3D culture system to evaluate the therapeutic efficacy of epigallocatechin gallate (EGCG), a plant-based natural compound, in head and neck cancer cells. Our findings reveal that the sensitivity of natural products in 3D culture models may differ markedly from that obtained using 2D cultures, suggesting that 3D models will become a more reliable alternative to minimize misleading data.

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.

BACKGROUND: Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. METHODS: A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate. RESULTS: We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. CONCLUSIONS: These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3.

BACKGROUND: Metastasis is most often the root cause of cancer-related death. Human short stature homeobox 2 (SHOX2), a homeodomain transcription factor, is a novel inducer of epithelial-to-mesenchymal transition in breast cancer cells, though its exact role and underlying mechanisms in metastasis are not well understood. METHODS: TCGA analysis was performed to identify the clinical relevance of SHOX2 in breast cancer. Gene depletion was achieved by short hairpin RNA and small interfering RNA. Molecular regulations and alterations were assessed by Western blotting, immunoprecipitation, immunohistochemistry, qRT-PCR, chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR), and ChIP/re-ChIP. The impact of SHOX2 signaling on tumor growth and metastasis was evaluated in orthotopic breast tumor mice. RESULTS: The expression level of SHOX2 is strongly associated with poor distant metastasis-free survival in breast cancer patients and inactivation of SHOX2 suppresses breast tumor growth and metastasis in mice. In breast cancer cells, SHOX2 directly activates Wiskott-Aldridge syndrome protein family member 3 (WASF3), a metastasis-promoting gene, at the transcriptional level, leading to a significant increase in metastatic potential. Mechanistically, SHOX2 activates signal transducer and activator of transcription 3 (STAT3) and recruits it to the WASF3 promoter, where STAT3 cooperates with SHOX2 to form a functional immunocomplex to promote WASF3 transcriptional activity in breast cancer cells. WASF3 knockdown abrogates SHOX2-induced metastasis, but not SHOX2-dependent tumorigenesis. CONCLUSIONS: These findings provide a critical link between the SHOX2-STAT3-WASF3 signaling axis and metastasis and suggest that the targeting of this signaling node may represent a valuable alternative strategy for combating breast cancer metastasis.

FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis.

BACKGROUND: There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. METHODS: Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice. RESULTS: The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527. CONCLUSIONS: Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

Multifaceted Roles of Long Non-coding RNAs in Head and Neck Cancer.

The majority of RNA transcripts are non-coding RNA (ncRNA) transcripts with lengths exceeding 200 nucleotides that are not translated into protein. Unlike microRNAs (miRNAs), long ncRNAs (lncRNAs) are not confined to a single mechanism of action but have a large and diverse role in biological processes as they can function as transcription regulators, decoys, scaffolds, and enhancer RNAs. Currently, many lncRNA molecules are under investigation for their role in tumorigenesis, metastasis, and prognosis in different types of cancer. This review not only summarizes the characteristics and functions of lncRNAs but also discusses the therapeutic implications and applications of lncRNAs with roles associated with head and neck cancer. Our aim is to pinpoint the potential way to perturb specific lncRNAs for future therapeutic use.

PI3K Isoform-Selective Inhibitors in Cancer.

PI3K inhibitors are a common area of research in finding a successful treatment of cancer. The PI3K pathway is important for cell growth, apoptosis, cell metabolism, cell survival, and a multitude of other functions. There are multiple isoforms of PI3K that can be broken down into three categories: class I, II, and III. Each isoform has at least one subunit that helps with the functionality of the isoform. Mutations found in the PI3K isoforms are commonly seen in many different types of cancer and the use of inhibitors is being tested to stop the cell survival of cancer cells. Individual PI3K inhibitors have shown some inhibition of the pathway; however, there is room for improvement. To better treat cancer, PI3K inhibitors are being combined with other pathway inhibitors. These combination therapies have shown better results with cancer treatments. Both the monotherapy and dual therapy treatments are still currently being studied and data collected to better understand cancer and other treatment options.

Targeting ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Cancer.

The control of crosstalk between autophagy and apoptosis in tumor cells can remove a critical barrier to comprehensive and efficacious treatment for cancer. Reactive oxygen species (ROS), by-products of redox homeostasis, are critical for regulating the balance between autophagy and apoptosis in cancer cells upon different drug treatments and gene modifications. The mechanisms and consequences involved in ROS-mediated crosstalk between apoptosis and autophagy are extremely complex in cancer cells. Here, we mainly discuss the closely linked relationship between ROS levels, autophagy, and apoptosis in cancer therapy.

Visualizing and Evaluating Cancer Cell Growth and Invasion by a Novel 3D Culture System.

With the development of new materials and technologies, it is possible to access gene function and drug metabolism using a three-dimensional (3D) cell culture system, which is more suitable for mimicking the in vivo microenvironment of cultured tumor cells ex vivo. SeedEZ is a novel and versatile tool that allows culturing of different types of cells with user convenience and in a desired sequence. This system provides a bridge between traditional 2D culture and animal experiments. Here, we provide two examples demonstrating how to evaluate cancer cell growth by the SeedEZ 3D scaffold and cancer cell invasion by the SeedEZ 3D ring, in order to promote understanding of the necessity of this novel cell culture system.

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib.

BACKGROUND: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. METHODS: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. CONCLUSIONS: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

Unveiling Tumor Microenvironment Interactions Using Zebrafish Models.

The tumor microenvironment (TME) is a rich and active arena that is strategically evolved overtime by tumors to promote their survival and dissemination. Over the years, attention has been focused to characterize and identify the tumor-supporting roles and subsequent targeting potentials of TME components. Nevertheless, recapitulating the human TME has proved inherently challenging, leaving much to be explored. In this regard, in vivo model systems like zebrafish, with its optical clarity, ease of genetic manipulation, and high engraftment, have proven to be indispensable for TME modeling and investigation. In this review, we discuss the recent ways by which zebrafish models have lent their utility to provide new insights into the various cellular and molecular mechanisms driving TME dynamics and tumor support. Specifically, we report on innate immune cell interactions, cytokine signaling, metastatic plasticity, and other processes within the metastatic cascade. In addition, we reflect on the arrival of adult zebrafish models and the potential of patient-derived xenografts.

Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma.

BACKGROUND: Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted. METHODS: Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS: Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells. CONCLUSIONS: Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.

Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.

BACKGROUND: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. METHODS: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. RESULTS: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. CONCLUSIONS: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

PFKP Signaling at a Glance: An Emerging Mediator of Cancer Cell Metabolism.

Phosphofructokinase-1 (PFK-1), a rate-determining enzyme of glycolysis, is an allosteric enzyme that regulates the oxidation of glucose in cellular respiration. Glycolysis phosphofructokinase platelet (PFKP) is the platelet isoform and works as an important mediator of cell metabolism. Considering that PFKP is a crucial player in many steps of cancer initiation and metastasis, we reviewed the specificities and complexities of PFKP and its biological roles in human diseases, especially malignant tumors. The possible use of PFKP as a diagnostic marker or a drug target in the prevention or treatment of cancer is also discussed.