Adaptor Proteins Mediate CXCR4 and PI4KA Crosstalk in Prostate Cancer Cells and the Significance of PI4KA in Bone Tumor Growth

Overview

Journal Sci Rep

Specialty Science

Date 2023 Nov 23

PMID 37996444

Authors

Barani Govindarajan

Diego Sbrissa

Mark Pressprich

Seongho Kim

Arun K Rishi

Ulka Vaishampayan

Michael L Cher

Sreenivasa R Chinni

Affiliations

Soon will be listed here.

Abstract

The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.

Citing Articles

Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review).

Xu Y, Zhang G, Liu Y, Liu Y, Tian A, Che J Int J Oncol. 2024; 65(5).

PMID: 39301646 PMC: 11419411. DOI: 10.3892/ijo.2024.5692.

A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P.

Bura A, cabrijan S, Duric I, Bruketa T, Jurak Begonja A Cells. 2023; 12(10).

PMID: 37408244 PMC: 10216963. DOI: 10.3390/cells12101411.

References

Stultz J, Fong L . How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer. Prostate Cancer Prostatic Dis. 2021; 24(3):697-717. PMC: 8384622. DOI: 10.1038/s41391-021-00340-5. View

Balla A, Kim Y, Varnai P, Szentpetery Z, Knight Z, Shokat K . Maintenance of hormone-sensitive phosphoinositide pools in the plasma membrane requires phosphatidylinositol 4-kinase IIIalpha. Mol Biol Cell. 2007; 19(2):711-21. PMC: 2230591. DOI: 10.1091/mbc.e07-07-0713. View

Cai J, Kandagatla P, Singareddy R, Kropinski A, Sheng S, Cher M . Androgens Induce Functional CXCR4 through ERG Factor Expression in TMPRSS2-ERG Fusion-Positive Prostate Cancer Cells. Transl Oncol. 2010; 3(3):195-203. PMC: 2887649. DOI: 10.1593/tlo.09328. View

Wang Z, Ma Q, Liu Q, Yu H, Zhao L, Shen S . Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway. Br J Cancer. 2008; 99(10):1695-703. PMC: 2584946. DOI: 10.1038/sj.bjc.6604745. View

Ratajczak M, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, Ratajczak J . The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia. 2006; 20(11):1915-24. DOI: 10.1038/sj.leu.2404357. View

Burger J, Kipps T . CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2005; 107(5):1761-7. DOI: 10.1182/blood-2005-08-3182. View

Chinni S, Sivalogan S, Dong Z, Trindade Filho J, Deng X, Bonfil R . CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate. 2005; 66(1):32-48. DOI: 10.1002/pros.20318. View

Kattan W, Liu J, Montufar-Solis D, Liang H, Barathi B, van der Hoeven R . Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer. Proc Natl Acad Sci U S A. 2021; 118(51). PMC: 8713765. DOI: 10.1073/pnas.2114126118. View

Tomlins S, Laxman B, Varambally S, Cao X, Yu J, Helgeson B . Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia. 2008; 10(2):177-88. PMC: 2244693. DOI: 10.1593/neo.07822. View

10.

Steen C, Liu C, Alizadeh A, Newman A . Profiling Cell Type Abundance and Expression in Bulk Tissues with CIBERSORTx. Methods Mol Biol. 2020; 2117:135-157. PMC: 7695353. DOI: 10.1007/978-1-0716-0301-7_7. View

11.

Shiozawa Y, Pedersen E, Havens A, Jung Y, Mishra A, Joseph J . Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011; 121(4):1298-312. PMC: 3069764. DOI: 10.1172/JCI43414. View

12.

Bojjireddy N, Guzman-Hernandez M, Reinhard N, Jovic M, Balla T . EFR3s are palmitoylated plasma membrane proteins that control responsiveness to G-protein-coupled receptors. J Cell Sci. 2014; 128(1):118-28. PMC: 4282049. DOI: 10.1242/jcs.157495. View

13.

Singareddy R, Semaan L, Conley-LaComb M, St John J, Powell K, Iyer M . Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2-ERG fusions. Mol Cancer Res. 2013; 11(11):1349-61. PMC: 3901058. DOI: 10.1158/1541-7786.MCR-12-0705. View

14.

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

15.

Adhikari H, Kattan W, Kumar S, Zhou P, Hancock J, Counter C . Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nat Commun. 2021; 12(1):5248. PMC: 8429657. DOI: 10.1038/s41467-021-25523-5. View

16.

Singh A, Arora S, Bhardwaj A, Srivastava S, Kadakia M, Wang B . CXCL12/CXCR4 protein signaling axis induces sonic hedgehog expression in pancreatic cancer cells via extracellular regulated kinase- and Akt kinase-mediated activation of nuclear factor κB: implications for bidirectional tumor-stromal interactions. J Biol Chem. 2012; 287(46):39115-24. PMC: 3493952. DOI: 10.1074/jbc.M112.409581. View

17.

Chinni S, Yamamoto H, Dong Z, Sabbota A, Bonfil R, Cher M . CXCL12/CXCR4 transactivates HER2 in lipid rafts of prostate cancer cells and promotes growth of metastatic deposits in bone. Mol Cancer Res. 2008; 6(3):446-57. PMC: 3842603. DOI: 10.1158/1541-7786.MCR-07-0117. View

18.

Chu C, Cha S, Lin W, Lu P, Tan C, Chang C . Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-kappaB/interleukin-6 pathway. Carcinogenesis. 2008; 30(2):205-13. DOI: 10.1093/carcin/bgn228. View

19.

Hughes R, Qian B, Rowan C, Muthana M, Keklikoglou I, Olson O . Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. Cancer Res. 2015; 75(17):3479-91. PMC: 5024531. DOI: 10.1158/0008-5472.CAN-14-3587. View

20.

Arwert E, Harney A, Entenberg D, Wang Y, Sahai E, Pollard J . A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation. Cell Rep. 2018; 23(5):1239-1248. PMC: 5946803. DOI: 10.1016/j.celrep.2018.04.007. View