The Multifaceted Role of Phafin Proteins in Cancer: A Comprehensive Review of Their Functions, Mechanisms, and Therapeutic Potential Across Various Tumor Types
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Keywords

Phafin proteins
Cancers
Treatment
Diagnosis

DOI

10.26689/ijgpn.v2i3.8171

Submitted : 2024-08-19
Accepted : 2024-09-03
Published : 2024-09-18

Abstract

Phafin proteins, specifically Phafin1 and Phafin2, have recently emerged as critical players in cancer biology due to their involvement in essential cellular processes such as autophagy, apoptosis, and signal transduction. Phafin1, characterized by its pleckstrin homology (PH) domain and FYVE domain, regulates autophagy and apoptosis, thereby influencing cancer cell survival and proliferation. Dysregulation of Phafin1-mediated autophagy and its interaction with pro-apoptotic proteins like Bax contribute to apoptosis resistance in various cancers, including breast and lung cancer. Phafin2, sharing structural similarities with Phafin1, plays roles in endosomal trafficking and signaling pathways, enhancing cancer cell migration and invasion, particularly in colorectal and gastric cancers. Elevated levels of Phafin proteins correlate with poor prognosis and chemoresistance, underscoring their potential as diagnostic markers and therapeutic targets. Targeting Phafin proteins through small molecule inhibitors or monoclonal antibodies presents a promising therapeutic strategy, aiming to restore the balance between autophagy and apoptosis in cancer cells. This review synthesizes recent research on Phafin proteins, highlighting their molecular mechanisms, roles in specific cancers, and potential clinical applications, providing a comprehensive understanding of their significance in cancer biology and therapy.

References

Hasan M, Capelluto DG, 2022, The PH Domain and C-Terminal polyD Motif of Phafin2 Exhibit a Unique Concurrence in Animals. Membranes, 12(7): 696.

Posor Y, Jang W, Haucke V, 2022, Phosphoinositides as Membrane Organizers. Nature Reviews Molecular Cell Biology, 23(12): 797–816.

Tang T, Hasan M, Capelluto DG, 2023, Phafins are more than Phosphoinositide-Binding Proteins. International Journal of Molecular Sciences, 24(9): 8096.

Overduin M, Kervin TA, 2021, The Phosphoinositide Code is Read by a Plethora of Protein Domains. Expert Review of Proteomics, 18(7): 483–502.

Tang T, Hasan M, Capelluto DG, 2023, Phafins are more than Phosphoinositide-Binding Proteins. International Journal of Molecular Sciences, 24(9): 8096.

Tang T, 2021, Phosphatidylinositol 3-phosphate Binding Properties and Autoinhibition Mechanism of Phafin2, thesis, Virginia Polytechnic Institute and State University.

Kim A, Cunningham KW, 2015, A LAPF/phafin1-like Protein Regulates TORC1 and Lysosomal Membrane Permeabilization in Response to Endoplasmic Reticulum Membrane Stress. Molecular Biology of the Cell, 26(25): 4631–4645.

Lin WJ, Yang CY, Li LL et al., 2012, Lysosomal Targeting of phafin1 Mediated by Rab7 Induces Autophagosome Formation. Biochemical and Biophysical Research Communications, 417(1): 35–42.

Li C, Liu Q, Li N, et al. 2008, EAPF/Phafin-2, a Novel Endoplasmic Reticulum-associated Protein, Facilitates TNF-a-triggered Cellular Apoptosis through Endoplasmic Reticulum-Mitochondrial Apoptotic Pathway. Journal of Molecular Medicine, 2008(86): 471–484.

Tang T, Sun J, Li C, 2024, The Role of Phafin Proteins in Cell Signaling Pathways and Diseases. Open Life Sciences, 19(1): 20220896.

Hasan M, 2024, Domain-based Bioinformatics Analysis and Molecular Insights for the Autoregulatory Mechanism of Phafin2, thesis, Virginia Tech.

Kim A, Cunningham KW, A LAPF/phafin1-like Protein Regulates TORC1 and Lysosomal Membrane Permeabilization in Response to ER Membrane Stress. Molecular Biology of the Cell, 26(25): 4631–4645.

Lin WJ, Yang CY, Li LL et al., 2012, Lysosomal Targeting of phafin1 Mediated by Rab7 Induces Autophagosome Formation. Biochemical and Biophysical Research Communications, 417(1): 35–42.

Lin WJ, Yang CY, Li LL et al., 2012, Lysosomal Targeting of phafin1 Mediated by Rab7 Induces Autophagosome Formation. Biochemical and Biophysical Research Communications, 417(1): 35–42.

Yan L, Hou C, Liu J, et al., 2023, Local Administration of Liposomal-based Plekhf1 Gene Therapy Attenuates Pulmonary Fibrosis by Modulating Macrophage Polarization. Science China Life Sciences, 66(11): 2571–2586.

Li C, Liu Q, Li N, et al., 2008, EAPF/Phafin-2, A Novel Endoplasmic Reticulum-associated Protein, Facilitates TNF-a-triggered Cellular Apoptosis through Endoplasmic Reticulum-Mitochondrial Apoptotic Pathway. Journal of Molecular Medicine, 2008(86): 471–484.

Schink KO, Tan KW, Spangenberg H, et al., 2021, The Phosphoinositide Coincidence Detector Phafin2 promotes Macropinoc Tosis b Coordinating Actin Organisation at Forming Macropinosomes. Nature Communications, 12(1): 6577.

Chen W, Li N, Chen T, et al., 2005, The Lysosome-associated Apoptosis-inducing Protein Containing the Pleckstrin Homology (PH) and FYVE Domains (LAPF), Representative of a Novel Family of PH and FYVE Domain-containing Proteins, Induces Caspase-independent Apoptosis via the Lysosomal-mitochondrial Pathway. Journal of Biological Chemistry, 280(49): 40985–40995.

Natrajan R, Mackay A, Wilkerson PM, et al., 2012, Functional Characterization of the 19q12 Amplicon in Grade III Breast Cancers. Breast Cancer Research, 14(2): 1–15.

Su P, Peng Z, Xu B, et al., 2021, Establishment and Validation of an Individualized Macrophage-related Gene Signature to Predict Overall Survival in Patients with Triple Negative Breast Cancer. PeerJ, 2021(9): e12383.

Andrieu-Abadie N, 2009, Lysosomal Proteases in Cell Death, in Essentials of Apoptosis: A Guide for Basic and Clinical Research. Springer, New York, 647–669.

Mondal P, Natesh J, Penta D, et al., 2022, Extract of Murraya koenigii Selectively Causes Genomic Instability by Altering Redox-status via Targeting PI3K/AKT/Nrf2/caspase-3 Signaling Pathway in Human non-small Cell Lung Cancer. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2022(104): 154272.

Yan L, Hou C, Liu J, et al., 2023, Local Administration of Liposomal-based Plekhf1 Gene Therapy Attenuates Pulmonary Fibrosis by Modulating Macrophage Polarization. Science China Life Sciences, 66(11): 2571–2586.

Neklason DW, Done MW, Milash B, et al., 2011, Deciphering the Molecular Pathways Disrupted in Normal and Neoplastic Colonic Tissue in Inherited Colorectal Cancer Syndromes. Hereditary Cancer in Clinical Practice, 9(6): 1–2.

Schink KO, Tan KW, Spangenberg H, et al., 2021, The Phosphoinositide Coincidence Detector Phafin2 Promotes Macropinocytosis by Coordinating Actin Organisation at Forming Macropinosomes. Nature Communications, 12(1): 6577.

Romero-Garcia S, Prado-Garcia H, 2019, Mitochondrial Calcium: Transport and Modulation of Cellular Processes in Homeostasis and Cancer. International Journal of Oncology, 54(4): 1155–1167.

Fu H, Wang C, Yang D, et al., 2018, Curcumin Regulates Proliferation, Autophagy, and Apoptosis in Gastric Cancer Cells by Affecting PI3K and P53 Signaling. Journal of Cellular Physiology, 233(6): 4634–4642.

Ellena JF, Tang TX, Shanaiah N, et al., 2022, Backbone 1H, 15N, and 13C Resonance Assignments of the Phafin2 Pleckstrin Homology Domain. Biomolecular NMR assignments, 16(1): 27–30.

Basu A, Lambring CB, 2021, Akt Isoforms: A Family Affair in Breast Cancer. Cancers, 13(14): 3445.

Zheng M, Long J, Chelariu-Raicu A, 2021, Identification of a Novel Tumor Microenvironment Prognostic Signature for Advanced-stage Serous Ovarian Cancer. Cancers, 13(13): 3343.

Guan X, Guan X, Dong C, et al., 2020, Rho GTPases and related Signaling Complexes in Cell Migration and Invasion. Experimental Cell Research, 388(1): 111824.

Culig Z, Santer FR, 2014, Androgen Receptor Signaling in Prostate Cancer. Cancer and Metastasis Reviews, 2014(33): 413–427.

Andrieu-Abadie N, 2009, Lysosomal Proteases in Cell Death, in Essentials of Apoptosis: A Guide for Basic and Clinical Research. Springer, New York, 647–669.

Yan L, Hou C, Liu J, et al., 2023, Local Administration of Liposomal-based Plekhf1 Gene Therapy Attenuates Pulmonary Fibrosis by Modulating Macrophage Polarization. Science China Life Sciences, 66(11): 2571–2586.

Ren Y, Wang C, Wang H, et al., 2022, Identification of Zebrafish PLEKHF2 Presents in Egg/embryos as an Antibacterial Protein. Fish & Shellfish Immunology, 2022(127): 925–932.

Gailite I, Egger-Adam D, Wodarz A, 2012, The Phosphoinositide-associated Protein Rush Hour Regulates Endosomal Trafficking in Drosophila. Molecular Biology of the Cell, 23(3): 433–447.