Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer

Abstract

The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.

Keywords

Phosphatase and tensin homolog / platelet-activating factor-receptor / epidermal growth factor receptor / cell signaling pathways / cancer therapy

References

[1] Mester J, Eng C. When overgrowth bumps into cancer: the PTEN—opathies. Am J Med Genet C Semin Med Genet. 2013; 163C: 114-21.

[2] Pérez—Ramírez C, Canãdas—Garre M, Molina MÁ, Faus—Dáder MJ, Calleja—Hernández MÁ. PTEN and PI3K/AKT in Non—Small—Cell Lung Cancer. Pharmacogenomics. 2015; 16: 1843—62.

[3] Vazquez F, Matsuoka S, Sellers WR, Yanagida T, Ueda M, Devreotes PN. Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane. Proc Natl Acad Sci U S A. 2006; 103: 3633-8.

[4] Wang Q, Wang J, Xiang H, Ding P, Wu T, Ji G. The biochemical and clinical implications of phosphatase and tensin homolog deleted on chromosome ten in different cancers. Am J Cancer Res. 2021; 11: 5833-55.

[5] Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, et al. A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science. 2013; 341: 399-402.

[6] Zheng C, Tang F, Min L, Hornicek F, Duan Z, Tu C. PTEN in osteosarcoma: Recent advances and the therapeutic potential. Biochim Biophys Acta Rev Cancer. 2020; 1874: 188405.

[7] Sirhan Z, Alojair R, Thyagarajan A, Sahu RP. Therapeutic Implications of PTEN in Non—Small Cell Lung Cancer. Pharmaceutics. 2023; 15: 2090.

[8] da Silva—Jr IA, Chammas R, Lepique AP, Jancar S. Platelet—activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy. Oncogenesis. 2017; 6: e296.

[9] Sahu RP, Ocana JA, Harrison KA, Ferracini M, Touloukian CE, Al—Hassani M, et al. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet—activating factor. Cancer Res. 2014; 74: 7069-78.

[10] Sahu RP, Konger RL, Travers JB. Platelet—Activating Factor—Receptor and Tumor Immunity. JSM Cell Dev Biol. 2014; 2: 1008.

[11] Travers JB, Rohan JG, Sahu RP. New Insights Into the Pathologic Roles of the Platelet—Activating Factor System. Front Endocrinol (Lausanne). 2021; 12: 624132.

[12] Chen J, Lan T, Zhang W, Dong L, Kang N, Zhang S, et al. Feed—Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial—Mesenchymal Transition in Non—Small Cell Lung Cancer. Cancer Res. 2015; 75: 4198-210.

[13] Chen J, Lan T, Zhang W, Dong L, Kang N, Zhang S, et al. Platelet—activating factor receptor—mediated PI3K/AKT activation contributes to the malignant development of esophageal squamous cell carcinoma. Oncogene. 2015; 34: 5114—27.

[14] Sahu RP, Harrison KA, Weyerbacher J, Murphy RC, Konger RL, Garrett JE, et al. Radiation therapy generates platelet—activating factor agonists. Oncotarget. 2016; 7: 20788-800.

[15] Gajiwala KS, Feng J, Ferre R, Ryan K, Brodsky O, Weinrich S, et al. Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition. Structure. 2013; 21: 209—19.

[16] Colabufo NA, Contino M, Niso M, Berardi F, Leopoldo M, Perrone R. EGFR tyrosine kinase inhibitors and multidrug resistance: perspectives. Front Biosci (Landmark Ed). 2011; 16: 1811—23.

[17] Uribe ML, Marrocco I, Yarden Y. EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance. Cancers (Basel). 2021; 13: 2748.

[18] Zubair T, Bandyopadhyay D. Small Molecule EGFR Inhibitors as Anti—Cancer Agents: Discovery, Mechanisms of Action, and Opportunities. Int J Mol Sci. 2023; 24: 2651.

[19] Zhao M, Zhang J, Gao J, Wang J, Ma Z. Osimertinib Efficacy and Safety in Treating Epidermal Growth Factor Receptor Mutation—Positive Advanced Non—Small—Cell Lung Cancer: A Meta—Analysis. Clin Pharmacol Drug Dev. 2024;[Epub ahead of print].

[20] Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR—TKIs resistance via EGFR—independent signaling pathways. Mol Cancer. 2018; 17: 53.

[21] Lee J, Kim HS, Lee B, Kim HK, Sun J, Ahn JS, et al. Genomic landscape of acquired resistance to third—generation EGFR tyrosine kinase inhibitors in EGFR T790M—mutant non—small cell lung cancer. Cancer. 2020; 126: 2704-12.

[22] Kita Y, Shindou H, Shimizu T. Cytosolic phospholipase A₂ and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids. 2019; 1864: 838—45.

[23] Marathe GK, Prescott SM, Zimmerman GA, McIntyre TM. Oxidized LDL contains inflammatory PAF—like phospholipids. Trends Cardiovasc Med. 2001; 11: 139-42.

[24] Sahu RP, Petrache I, Demark MJV, Rashid BM, Ocana JA, Tang Y, et al. Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet—activating factor agonists. J Immunol. 2013; 190: 2447-54.

[25] Silva Junior IAd, Stone SC, Rossetti RM, Jancar S, Lepique AP. Modulation of Tumor—Associated Macrophages (TAM) Phenotype by Platelet—Activating Factor (PAF) Receptor. J Immunol Res. 2017; 2017: 5482768.

[26] Thyagarajan A, Alshehri MSA, Miller KLR, Sherwin CM, Travers JB, Sahu RP. Myeloid—Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches. Cancers (Basel). 2019; 11: 1627.

[27] Thyagarajan A, Kadam SM, Liu L, Kelly LE, Rapp CM, Chen Y, et al. Gemcitabine Induces Microvesicle Particle Release in a Platelet—Activating Factor—Receptor—Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells. Int J Mol Sci. 2018; 20: 32.

[28] Chauhan SJ, Thyagarajan A, Chen Y, Travers JB, Sahu RP. Platelet—Activating Factor—Receptor Signaling Mediates Targeted Therapies—Induced Microvesicle Particles Release in Lung Cancer Cells. Int J Mol Sci. 2020; 21: 8517.

[29] Cellai C, Laurenzana A, Vannucchi AM, Caporale R, Paglierani M, Lollo SD, et al. Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB—2086. Br J Cancer. 2006; 94: 1637—42.

[30] Bussolati B, Biancone L, Cassoni P, Russo S, Rola—Pleszczynski M, Montrucchio G, et al. PAF produced by human breast cancer cells promotes migration and proliferation of tumor cells and neo—angiogenesis. Am J Pathol. 2000; 157: 1713-25.

[31] Kim H, Kim K, Seo KH, Lee H, Im S. PTEN/MAPK pathways play a key role in platelet—activating factor—induced experimental pulmonary tumor metastasis. FEBS Lett. 2012; 586: 4296-302.

[32] Alshehri E, Al—Dogmi AM, Al—Hazani TMI, Alwaili MA, Safhi FA, Alneghery LM, et al. Patterns of mutations in nine cancer—related genes and PAF development among smoking male patients diagnosed with bladder cancer. Tumour Biol. 2023; 45: 1-14.

[33] Kang N, Yoon H, Kim H, Kim K, Han M, Lee Y, et al. Protein kinase CK2/PTEN pathway plays a key role in platelet—activating factor—mediated murine anaphylactic shock. J Immunol. 2011; 186: 6625—32.

[34] Aponte M, Jiang W, Lakkis M, Li M, Edwards D, Albitar L, et al. Activation of platelet—activating factor receptor and pleiotropic effects on tyrosine phospho—EGFR/Src/FAK/paxillin in ovarian cancer. Cancer Res. 2008; 68: 5839-48.

[35] Yu Y, Zhang M, Zhang X, Cai Q, Zhu Z, Jiang W, et al. Transactivation of epidermal growth factor receptor through platelet—activating factor/receptor in ovarian cancer cells. J Exp Clin Cancer Res. 2014; 33: 85.

[36] Yu Y, Zhang M, Zhang X, Cai Q, Hong S, Jiang W, et al. Synergistic effects of combined platelet—activating factor receptor and epidermal growth factor receptor targeting in ovarian cancer cells. J Hematol Oncol. 2014; 7: 39.

[37] Yu Y, Zhang X, Hong S, Zhang M, Cai Q, Jiang W, et al. Epidermal growth factor induces platelet—activating factor production through receptors transactivation and cytosolic phospholipase A2 in ovarian cancer cells. J Ovarian Res. 2014; 7: 39.

[38] Yao Y, Wolverton JE, Zhang Q, Marathe GK, Al—Hassani M, Konger RL, et al. Ultraviolet B radiation generated platelet—activating factor receptor agonist formation involves EGF—R—mediated reactive oxygen species. J Immunol. 2009; 182: 2842—8.

[39] Souza JL, Martins—Cardoso K, Guimarães IS, Melo ACd, Lopes AH, Monteiro RQ, et al. Interplay Between EGFR and the Platelet—Activating Factor/PAF Receptor Signaling Axis Mediates Aggressive Behavior of Cervical Cancer. Front Oncol. 2020; 10: 557280.

[40] Morimoto R, Shindou H, Oda Y, Shimizu T. Phosphorylation of lysophosphatidylcholine acyltransferase 2 at Ser34 enhances platelet—activating factor production in endotoxin—stimulated macrophages. J Biol Chem. 2010; 285: 29857-62.

[41] Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45: W98-102.