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Phospholipase Family Enzymes in Lung Cancer: Looking for Novel Therapeutic Approaches

CANCERS (2023)

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Review Biochemistry & Molecular Biology

The Phospholipase A2 Superfamily: Structure, Isozymes, Catalysis, Physiologic and Pathologic Roles

Shibbir Ahmed Khan et al.

Summary: The phospholipase A2 (PLA2) superfamily is a group of enzymes that hydrolyze phospholipids by breaking the ester bond at the sn-2 position, resulting in the production of free fatty acids and lysophospholipids at the water/lipid interface. PLA2s are amphiphilic and act on phospholipid assemblies rather than isolated single phospholipids. This review focuses on the different families of PLA2 isoenzymes, including secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca2+-independent PLA2 (iPLA2), lipoprotein-associated PLA2 (LpPLA2), lysosomal PLA2 (LPLA2), and adipose-tissue-specific PLA2 (AdPLA2), discussing their structural differences, mechanism of action, substrate specificity, interfacial kinetics, and tissue distribution. The expression of PLA2s has been found to increase significantly in various diseases such as sepsis, inflammation, cancers, glaucoma, obesity, and Alzheimer's disease, which are also covered in this review.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

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Article Biochemistry & Molecular Biology

MiR-17-3p Facilitates Aggressive Cell Phenotypes in Colon Cancer by Targeting PLCD1 Through Affecting KIF14

Jinxing Ji et al.

Summary: The study demonstrated that miR-17-3p enhances the progression of colon cancer by downregulating PLCD1.

APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY (2023)

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Article Oncology

Cancer statistics, 2022

Rebecca L. Siegel et al.

Summary: Each year, the American Cancer Society compiles data on cancer occurrence and outcomes in the United States. The latest data shows that breast and prostate cancer progress has stagnated, while lung cancer has shown improvements in survival rates. Lung cancer incidence for advanced disease has declined while localized-stage rates have increased, resulting in higher survival rates. Mortality patterns align with incidence trends, with lung cancer deaths declining rapidly, breast cancer deaths slowing, and prostate cancer deaths stabilizing.

CA-A CANCER JOURNAL FOR CLINICIANS (2022)

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Article Plant Sciences

Emodin induces apoptosis and suppresses non-small-cell lung cancer growth via downregulation of sPLA2-IIa

Fang-Yuan Zhang et al.

Summary: Emodin exhibited a novel anti-tumor mechanism by decreasing the expression levels of sPLA2-IIa and NF-kappa B pathways, thus inhibiting the proliferation of KRAS mutant cell lines in non-small-cell lung cancer (NSCLC). This suggests that emodin could potentially serve as a therapeutic target in NSCLC.

PHYTOMEDICINE (2022)

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Review Immunology

Phosphatidylcholine-Derived Lipid Mediators: The Crosstalk Between Cancer Cells and Immune Cells

Renata de Freitas Saito et al.

Summary: This review highlights the role of phosphatidylcholine metabolism in cancer therapy resistance, from intracellular processes to cellular communication within the tumor microenvironment, providing new insights for treating drug-resistant cancers.

FRONTIERS IN IMMUNOLOGY (2022)

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Article Oncology

Aldolase A and Phospholipase D1 Synergistically Resist Alkylating Agents and Radiation in Lung Cancer

Yu-Chan Chang et al.

Summary: Exposure to alkylating agents and radiation can cause damage and apoptosis in cancer cells, but also leads to resistance and metabolic reprogramming. This study reveals the dominant role of phospholipase D1 (PLD1) in these processes, affecting cancer cell proliferation, autophagy, and DNA repair capabilities by regulating specific metabolites lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC). Additionally, aldolase A (ALDOA) inhibits PLD2 and enhances PLD1 and other carcinogenic features through protein-protein interaction (PPI). The combination of ALDOA and PLD1 serves as an independent prognostic factor in lung cancer and is correlated with clinical parameters.

FRONTIERS IN ONCOLOGY (2022)

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Article Oncology

Mutation-tailored treatment selection in non-small cell lung cancer patients in daily clinical practice

Elisabeth M. P. Steeghs et al.

Summary: This study evaluated molecular testing and treatment selection in stage IV NSCLC patients in the Netherlands. The results showed that predictive molecular testing rates were highest for adenocarcinomas and lowest for squamous cell carcinomas. Next-generation sequencing (NGS) approaches had a higher detection rate of therapeutic alterations compared to non-NGS approaches.

LUNG CANCER (2022)

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Review Biochemistry & Molecular Biology

Current Knowledge on Mammalian Phospholipase A1, Brief History, Structures, Biochemical and Pathophysiological Roles

Shun Yaginuma et al.

Summary: Phospholipase A(1) (PLA(1)) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. It plays an important role in maintaining the normal physiological functions of organisms.

MOLECULES (2022)

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Article Genetics & Heredity

Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology

Elio Adib et al.

Summary: There is significant variability in the prevalence of targetable genomic alterations in non-small cell lung cancer (NSCLC) patients according to genetic ancestry, histology, and smoking. Patients with squamous cell carcinoma (LUSC) and large cell carcinoma (LCLC) have 5% rates of targetable alterations, supporting the consideration for sequencing in these subtypes.

GENOME MEDICINE (2022)

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Article Oncology

Origin recognition complex 1 regulates phospholipase Cδ1 to inhibit cell proliferation, migration and epithelial-mesenchymal transition in lung adenocarcinoma

Yao Jian et al.

Summary: This study investigated the role of ORC1 in regulating PLCD1 in lung adenocarcinoma. The results showed that ORC1 may inhibit PLCD1 and thereby regulate the proliferation, migration, and EMT processes of lung adenocarcinoma cells. These findings suggest that ORC1 could be a potential target for the treatment of lung adenocarcinoma.

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Progress & Prospect of Enzyme-Mediated Structured Phospholipids Preparation

Yuhan Li et al.

Summary: In recent years, structured phospholipids (SPLs) have gained attention for their potential applications in pharmacy, food, cosmetics, and health. Compared to other lipid forms, SPLs have enhanced chemical, physical, and nutritional properties, and exhibit superior bioavailability. Enzyme-mediated SPLs preparation has advantages of product variety, substrate selectivity, and mild operation conditions. This review summarizes the progress in enzymatic modification of phospholipids over the last 20 years, including different reaction types and parameters affecting acyl migration. The article also proposes future prospects for the study of SPLs.

CATALYSTS (2022)

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Review Oncology

Economic Perspective of Cancer Care and Its Consequences for Vulnerable Groups

Joerg Haier et al.

Summary: For cancer patients, financial burdens and economic threats are common due to sociodemographic factors, rural/remote location and income. This economic vulnerability is associated with reduced utilization of cancer care and has an impact on outcomes. Financial burden is reported in many countries worldwide, and it needs to be addressed in order to provide sufficient quality of cancer care. Healthcare providers should pay attention to and address this vulnerability during the treatment of cancer patients.

CANCERS (2022)

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Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma

Alison L. Halpern et al.

Summary: The study found that the inhibition of sPLA2 IIa can reduce the expression of EGFR and HER2 in esophageal adenocarcinoma cells, thereby decreasing cell proliferation. In a mouse model, mice treated with sPLA2 IIa inhibitor had smaller tumors compared to the control group. This suggests the potential of sPLA2 IIa inhibitors as therapeutics in the treatment of esophageal adenocarcinoma.

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PLCD1 Suppressed Cellular Proliferation, Invasion, and Migration via Inhibition of Wnt/β-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma

Xin He et al.

Summary: The expression of PLCD1 was downregulated in ESCC cells compared to normal cells, and upregulation of PLCD1 inhibited proliferation, invasion, and migration of TE-1 and EC18 cells. PLCD1 activity was negatively associated with key proteins in the Wnt/beta-catenin signaling pathway. In vivo studies validated the inhibitory effects of PLCD1 on ESCC proliferation.

DIGESTIVE DISEASES AND SCIENCES (2021)

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Expression of Secretory Phospholipase A2 Group IIa in Breast Cancer and Correlation to Prognosis in a Cohort of Advanced Breast Cancer Patients

Sofie S. Jespersen et al.

Summary: The study investigated the expression of sPLA2-IIa in breast cancer patients, finding a high proportion of patients with elevated levels of sPLA2-IIa expression, and similar expression levels in primary tumors and metastases. The expression of sPLA2-IIa showed no correlation with clinicopathologic characteristics and prognosis in the patients.

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Supratim Mandal et al.

Summary: Phosphoinositide metabolism is a critical intracellular signaling system that regulates various biological functions, and PLCγ1, as a member of the PLC family, plays a crucial role in tumorigenesis by modulating cell survival, migration, invasion, and angiogenesis. The aberrant expression and regulation of PLCγ1 are linked to a range of deadly human cancers, highlighting its significance as a potential therapeutic target in cancer research. Further studies are needed to fully understand PLCγ1's precise role in carcinogenesis and its potential as a novel treatment target.

BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER (2021)

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Phospholipase A2 superfamily in cancer

Zhangxiao Peng et al.

Summary: Phospholipase A2 enzymes are a superfamily consisting of six subfamilies, playing important roles in inflammation-related diseases and cancer. Among them, sPLA2-IIA may have conflicting roles depending on cancer type, while cPLA2alpha and iPLA28 generally play a protumorigenic role in most cancers.

CANCER LETTERS (2021)

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Structure and regulation of phospholipase Cβ and ε at the membrane

Kaushik Muralidharan et al.

Summary: Phospholipase C (PLC) beta and epsilon enzymes hydrolyze phosphatidylinositol (PI) lipids in response to interactions with G protein subunits and small GTPases, generating second messengers that regulate intracellular Ca2+ concentration and activate PKC to affect physiological processes. The enzymes share a conserved core for lipase activity but utilize different strategies and structural elements to regulate their activity and interactions with membranes and G protein regulators.

CHEMISTRY AND PHYSICS OF LIPIDS (2021)

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Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer

Chen Chen et al.

Summary: Peroxiredoxin 6 (PRDX6), a bifunctional enzyme with GPx and iPLA2 activity, is highly expressed in various cancer cells, promoting tumorigenesis. Withangulatin A (WA) has been identified as a novel covalent inhibitor of PRDX6, binding to PRDX6 and inactivating its enzyme activity, showing potential in developing anti-tumor agents.

REDOX BIOLOGY (2021)

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Article Cell Biology

CXC chemokine ligand-13 promotes metastasis via CXCR5-dependent signaling pathway in non-small cell lung cancer

Chia-Chia Chao et al.

Summary: The study found that CXCL13 and CXCR5 were commonly up-regulated in lung cancer specimens, promoting migration of lung cancer cells through VCAM-1 expression. PLC beta, PKC alpha, and c-Src signaling pathways were involved in CXCL13-promoted cell migration and VCAM-1 expression in lung cancer cells. Additionally, CXCL13 stimulated NF-kappa B transcription factor, contributing to VCAM-1 expression at the translational level in lung cancer cells.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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Article Pharmacology & Pharmacy

Key Determinants of Health-Related Quality of Life Among Advanced Lung Cancer Patients: A Qualitative Study in Belgium and Italy

Rosanne Janssens et al.

Summary: Three main themes driving LC patients' HRQL were identified: physical aspects (symptoms and side-effects), psychological aspects (uncertainties about future health state), and social aspects (communication with healthcare providers and social interaction). Understanding these factors will aid patient-centric decision-making and address unmet needs in available treatment modalities.

FRONTIERS IN PHARMACOLOGY (2021)

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Review Cell Biology

Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?

Pravita Balijepalli et al.

Summary: Lysophosphatidic acid (LPA) is a family of phospholipids that act as ligands for G protein-coupled receptors, playing a significant role in cancer by stimulating cell proliferation and migration through multiple LPARs. Understanding the mechanisms underlying LPA signaling and its interactions with other receptors is crucial for drug discovery targeting GPCRs in cancer therapy.

CELLS (2021)

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Review Cell Biology

Phospholipase A2 Drives Tumorigenesis and Cancer Aggressiveness through Its Interaction with Annexin A1

Lara Vecchi et al.

Summary: This study discusses the crucial role of phospholipase A(2) (PLA(2)) in the development of the tumor microenvironment (TME) and the impact of Annexin A1 on its inhibitory function in the cancer context. Furthermore, the release of cancer-derived exosomes also contributes to the enrichment of PLA(2), COX-1, and COX-2 enzymes in TME, facilitating the formation of the tumor microenvironment.

CELLS (2021)

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Review Biochemistry & Molecular Biology

Peroxiredoxin-6: A Guardian of Lung Pathophysiologies

Anju Kumari et al.

Summary: Prdx-6, a moonlighting protein, plays important roles in maintaining normal lung physiologies and is implicated in various lung diseases, making it a potential common drug target for multiple lung diseases. Future insights have also been provided in the study.

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PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR

Soma Ghosh et al.

Summary: The research indicates that tumors with EGFR mutations have a lower response to immunotherapy, the EGFR pathway is associated with high PD-L1 expression and can promote an aggressive phenotype, while anti-PD-L1 antibodies can inhibit PD-L1 functions.

CELL REPORTS (2021)

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Oncogenic driver mutations in non-small cell lung cancer: Past, present and future

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Summary: Lung cancer, particularly non-small cell lung cancer, is the leading cause of cancer related-death globally, with alterations in oncogenic drivers playing a key role in cancer development. There are over fifteen targeted agents approved for treatment of non-small cell lung cancer, emphasizing the importance of understanding the biology and resistance mechanisms associated with each driver mutation for developing optimal treatment strategies.

WORLD JOURNAL OF CLINICAL ONCOLOGY (2021)

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SCD1 activity promotes cell migration via a PLD-mTOR pathway in the MDA-MB-231 triple-negative breast cancer cell line

Marine Lingrand et al.

BREAST CANCER (2020)

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Bihong T. Chen et al.

FRONTIERS IN ONCOLOGY (2020)

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Increased phospholipase D activity contributes to tumorigenesis in prostate cancer cell models

Mathieu Borel et al.

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Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer

Wenqiang Song et al.

MOLECULAR CANCER RESEARCH (2020)

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FGFR1 Is Critical for RBL2 Loss-Driven Tumor Development and Requires PLCG1 Activation for Continued Growth of Small Cell Lung Cancer

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CANCER RESEARCH (2020)

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PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia

Maria Saliakoura et al.

NATURE CELL BIOLOGY (2020)

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BIOMOLECULES (2020)

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Matilda Katan et al.

PROGRESS IN LIPID RESEARCH (2020)

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Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

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INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES (2020)

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS (2019)

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Shi-Hui Law et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2019)

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FRONTIERS IN PHARMACOLOGY (2019)

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Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, β-catenin, and Twist pathways

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Ectopic expression of PLC-β2 in non-invasive breast tumor cells plays a protective role against malignant progression and is correlated with the deregulation of miR-146a

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Genetic inactivation of the phospholipase A2 activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury

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Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2 Activity and Arachidonic Acid Production

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Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

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Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer

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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2015)

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Sasanka Ramanadham et al.

JOURNAL OF LIPID RESEARCH (2015)

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PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities

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Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

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Phospholipase A2 Enzymes: Physical Structure, Biological Function, Disease Implication, Chemical Inhibition, and Therapeutic Intervention

Edward A. Dennis et al.

CHEMICAL REVIEWS (2011)

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Review Biochemistry & Molecular Biology

Emerging roles for phospholipase A(2) enzymes in cancer

Kieran F. Scott et al.

BIOCHIMIE (2010)

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Article Oncology

Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 increased osteoclastogenesis

Ya-Ling Hsu et al.

CARCINOGENESIS (2010)

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Review Cell Biology

PKC and the control of localized signal dynamics

Carine Rosse et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2010)

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Review Oncology

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Elena B. Pasquale

NATURE REVIEWS CANCER (2010)

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Review Oncology

Lung Cancer in Never Smokers: Clinical Epidemiology and Environmental Risk Factors

Jonathan M. Samet et al.

CLINICAL CANCER RESEARCH (2009)

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Article Pharmacology & Pharmacy

Role of Ca2+-independent phospholipase A2 in cell growth and signaling

Shelley B. Hooks et al.

BIOCHEMICAL PHARMACOLOGY (2008)

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Article Oncology

Phospholipase Cγ1 Is Required for Metastasis Development and Progression

Gianluca Sala et al.

CANCER RESEARCH (2008)

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Article Oncology

Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines

Medhi Wangpaichitr et al.

MOLECULAR CANCER THERAPEUTICS (2008)

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Article Biochemistry & Molecular Biology

HIFα expression in VHL-deficient renal cancer cells is dependent on phospholipase

A. Toschi et al.

ONCOGENE (2008)

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Article Oncology

Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

Ming Shi et al.

CANCER LETTERS (2007)

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Article Endocrinology & Metabolism

Inositide-dependent phospholipase C signaling mimics insulin in skeletal muscle differentiation by affecting specific regions of the cyclin D3 promoter

Irene Faenza et al.

ENDOCRINOLOGY (2007)

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Article Biochemistry & Molecular Biology

Mutant p53 in MDA-MB-231 breast cancer cells is stabilized by elevated phospholipase D activity and contributes to survival signals generated by phospholipase D

L. Hui et al.

ONCOGENE (2006)

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Review Biochemistry & Molecular Biology

Coordinated intracellular translocation of phosphoinositide-specific phospholipase C-δ with the cell cycle

Hitoshi Yagisawa et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS (2006)

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Article Cell Biology

Expression of phospholipase C beta family isoenzymes in C2C12 myoblasts during terminal differentiation

I Faenza et al.

JOURNAL OF CELLULAR PHYSIOLOGY (2004)

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Article Biochemistry & Molecular Biology

Activation of phospholipase D by bradykinin and sphingosine 1-phosphate in A549 human lung adenocarcinoma cells via different GTP-binding proteins and protein kinase C delta signaling pathways

E Meacci et al.

BIOCHEMISTRY (2003)

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Article Neurosciences

Disruption of PLC-β1-mediated signal transduction in mutant mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration

D Böhm et al.

MOLECULAR AND CELLULAR NEUROSCIENCE (2002)

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Article Biochemistry & Molecular Biology

Elevated serum levels of interleukin-8 in advanced non-small cell lung cancer patients: Relationship with prognosis

M Orditura et al.

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH (2002)

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Article Biochemistry & Molecular Biology

Nuclear PLCβ1 acts as a negative regulator of p45/NF-E2 expression levels in Friend erythroleukemia cells

I Faenza et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2002)

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Article Biochemistry & Molecular Biology

Induction of cPLA2 in lung epithelial cells and non-small cell lung cancer is mediated by Sp1 and c-jun

SA Blaine et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2001)

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Article Biochemistry & Molecular Biology

Evidence for selective coupling of α1-adrenergic receptors to phospholipase C-β1 in rat neonatal cardiomyocytes

JF Arthur et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2001)

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Review Physiology

Structure, function, and control of phosphoinositide-specific phospholipase C

MJ Rebecchi et al.

PHYSIOLOGICAL REVIEWS (2000)

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Article Biochemistry & Molecular Biology

A role for nuclear phospholipase Cβ1 in cell cycle control

I Faenza et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2000)

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