The Hexosamine Biosynthetic Pathway Alters the Cytoskeleton to Modulate Cell Proliferation and Migration in Metastatic Prostate Cancer

Overview

Journal bioRxiv

Date 2024 Oct 28

PMID 39464080

Authors

Rajina Shakya

Praveen Suraneni

Alexander Zaslavsky

Amit Rahi

Christine B Magdongon

Raju Gajjela

Basil B Mattamana

Dileep Varma

Affiliations

Soon will be listed here.

Abstract

Castration-resistant prostate cancer (CRPC) progresses despite androgen deprivation therapy, as cancer cells adapt to grow without testosterone, becoming more aggressive and prone to metastasis. CRPC biology complicates the development of effective therapies, posing challenges for patient care. Recent gene-expression and metabolomics studies highlight the Hexosamine Biosynthetic Pathway (HBP) as a critical player, with key components like GNPNAT1 and UAP1 being downregulated in metastatic CRPC. GNPNAT1 knockdown has been shown to increase cell proliferation and metastasis in CRPC cell lines, though the mechanisms remain unclear. To investigate the cellular basis of these CRPC phenotypes, we generated a CRISPR-Cas9 knockout model of GNPNAT1 in 22Rv1 CRPC cells, analyzing its impact on metabolomic, glycoproteomic, and transcriptomic profiles of cells. We hypothesize that HBP inhibition disrupts the cytoskeleton, altering mitotic progression and promoting uncontrolled growth. GNPNAT1 KO cells showed reduced levels of cytoskeletal filaments, such as actin and microtubules, leading to cell structure disorganization and chromosomal mis-segregation. GNPNAT1 inhibition also activated PI3K/AKT signaling, promoting proliferation, and impaired cell adhesion by mislocalizing EphB6, enhancing migration via the RhoA pathway and promoting epithelial-to-mesenchymal transition. These findings suggest that HBP plays a critical role in regulating CRPC cell behavior, and targeting this pathway could provide a novel therapeutic approach.

References

Ren S, Shao Y, Zhao X, Hong C, Wang F, Lu X . Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer. Mol Cell Proteomics. 2015; 15(1):154-63. PMC: 4762514. DOI: 10.1074/mcp.M115.052381. View

Fu W, Hall M . Regulation of mTORC2 Signaling. Genes (Basel). 2020; 11(9). PMC: 7564249. DOI: 10.3390/genes11091045. View

Maccioni R, Cambiazo V . Role of microtubule-associated proteins in the control of microtubule assembly. Physiol Rev. 1995; 75(4):835-64. DOI: 10.1152/physrev.1995.75.4.835. View

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

Holland A, Cleveland D . Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep. 2012; 13(6):501-14. PMC: 3367240. DOI: 10.1038/embor.2012.55. View

Watson P, Arora V, Sawyers C . Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015; 15(12):701-11. PMC: 4771416. DOI: 10.1038/nrc4016. View

Le Minh G, Esquea E, Young R, Huang J, Reginato M . On a sugar high: Role of O-GlcNAcylation in cancer. J Biol Chem. 2023; 299(11):105344. PMC: 10641670. DOI: 10.1016/j.jbc.2023.105344. View

Hanover G, Vizeacoumar F, Banerjee S, Nair R, Dahiya R, Osornio-Hernandez A . Integration of cancer-related genetic landscape of Eph receptors and ephrins with proteomics identifies a crosstalk between EPHB6 and EGFR. Cell Rep. 2023; 42(7):112670. DOI: 10.1016/j.celrep.2023.112670. View

Logan C, Menko A . Microtubules: Evolving roles and critical cellular interactions. Exp Biol Med (Maywood). 2019; 244(15):1240-1254. PMC: 6880148. DOI: 10.1177/1535370219867296. View

10.

Gomez-Cebrian N, Poveda J, Pineda-Lucena A, Puchades-Carrasco L . Metabolic Phenotyping in Prostate Cancer Using Multi-Omics Approaches. Cancers (Basel). 2022; 14(3). PMC: 8833769. DOI: 10.3390/cancers14030596. View

11.

Coles C, Bradke F . Coordinating neuronal actin-microtubule dynamics. Curr Biol. 2015; 25(15):R677-91. DOI: 10.1016/j.cub.2015.06.020. View

12.

Zhang X, Tang N, Hadden T, Rishi A . Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011; 1813(11):1978-86. DOI: 10.1016/j.bbamcr.2011.03.010. View

13.

Rawla P . Epidemiology of Prostate Cancer. World J Oncol. 2019; 10(2):63-89. PMC: 6497009. DOI: 10.14740/wjon1191. View

14.

Godek K, Compton D . Quantitative methods to measure aneuploidy and chromosomal instability. Methods Cell Biol. 2018; 144:15-32. PMC: 6475901. DOI: 10.1016/bs.mcb.2018.03.002. View

15.

Liu B, Dong H, Lin X, Yang X, Yue X, Yang J . RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion. Oncotarget. 2016; 7(50):82411-82423. PMC: 5347701. DOI: 10.18632/oncotarget.12396. View

16.

Dehmelt L, Smart F, Ozer R, Halpain S . The role of microtubule-associated protein 2c in the reorganization of microtubules and lamellipodia during neurite initiation. J Neurosci. 2003; 23(29):9479-90. PMC: 6740480. View

17.

Bhowmick N, Ghiassi M, Bakin A, Aakre M, Lundquist C, Engel M . Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001; 12(1):27-36. PMC: 30565. DOI: 10.1091/mbc.12.1.27. View

18.

Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X . Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018; 17(1):104. PMC: 6060507. DOI: 10.1186/s12943-018-0856-3. View

19.

Chen Y, Chen S, Li K, Zhang Y, Huang X, Li T . Overdosage of Balanced Protein Complexes Reduces Proliferation Rate in Aneuploid Cells. Cell Syst. 2019; 9(2):129-142.e5. DOI: 10.1016/j.cels.2019.06.007. View

20.

Goodson H, Jonasson E . Microtubules and Microtubule-Associated Proteins. Cold Spring Harb Perspect Biol. 2018; 10(6). PMC: 5983186. DOI: 10.1101/cshperspect.a022608. View