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10.3390/cells14030192
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Article

Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response

by
Haley Dahl-Wilkie
1,
Jessica Gomez
1,
Anastasia Kelley
1,
Kirti Manjit
1,
Basir Mansoor
1,
Preethi Kanumuri
1,
Sammy Pardo
2,
Dana Molleur
2,
Rafah Falah
1,
Anisha R. Konakalla
1,
Morolake Omiyale
1,
Susan Weintraub
2 and
Nikki A. Delk
1,*
1
Biological Sciences Department, The University of Texas at Dallas, Richardson, TX 75080, USA
2
Department of Biochemistry & Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
*
Author to whom correspondence should be addressed.
Cells 2025, 14(3), 192; https://doi.org/10.3390/cells14030192
Submission received: 9 November 2024 / Revised: 25 January 2025 / Accepted: 26 January 2025 / Published: 28 January 2025
Versions Notes

Abstract

Chronic inflammation is a cancer hallmark and chronic exposure to interleukin-1 (IL-1) transforms castration-sensitive prostate cancer (PCa) cells into more fit castration-insensitive PCa cells. p62 is a scaffold protein that protects cells from nutrient deprivation via autophagy and from cytotoxic reactive oxygen via NFκB and NRF2 antioxidant signaling. Herein, we report that the LNCaP PCa cell line acquires high basal accumulation of the p62-KEAP1 complex when chronically exposed to IL-1. p62 promotes non-canonical NRF2 antioxidant signaling by binding and sequestering KEAP1 to the autophagosome for degradation. But despite high basal p62-KEAP1 accumulation, only two of several NRF2-induced genes analyzed, GCLC and HMOX1, showed high basal mRNA levels, suggesting that the high basal p62-KEAP1 accumulation does not result in overall high basal NRF2 activity. Nutrient starvation induces NRF2-dependent GCLC upregulation and HMOX1 repression, and we found that chronic IL-1-exposed LNCaP cells show hypersensitivity to serum starvation-induced GCLC and HMOX1 regulation. Thus, chronic IL-1 exposure affects cell response to nutrient stress. While HMOX1 expression remains NRF2/KEAP1-dependent in chronic IL-1-exposed LNCaP cells, GCLC expression is NRF2/KEAP1-independent. Furthermore, the high basal p62-KEAP1 complex accumulation is not required to regulate GCLC or HMOX1 expression, suggesting cells chronically exposed to IL-1 evolve a novel NRF2-independent role for the p62/KEAP1 axis.
Keywords: chronic IL-1; HMOX1; GCLC; p62-KEAP1; NRF2 chronic IL-1; HMOX1; GCLC; p62-KEAP1; NRF2

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MDPI and ACS Style

Dahl-Wilkie, H.; Gomez, J.; Kelley, A.; Manjit, K.; Mansoor, B.; Kanumuri, P.; Pardo, S.; Molleur, D.; Falah, R.; Konakalla, A.R.; et al. Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response. Cells 2025, 14, 192. https://doi.org/10.3390/cells14030192

AMA Style

Dahl-Wilkie H, Gomez J, Kelley A, Manjit K, Mansoor B, Kanumuri P, Pardo S, Molleur D, Falah R, Konakalla AR, et al. Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response. Cells. 2025; 14(3):192. https://doi.org/10.3390/cells14030192

Chicago/Turabian Style

Dahl-Wilkie, Haley, Jessica Gomez, Anastasia Kelley, Kirti Manjit, Basir Mansoor, Preethi Kanumuri, Sammy Pardo, Dana Molleur, Rafah Falah, Anisha R. Konakalla, and et al. 2025. "Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response" Cells 14, no. 3: 192. https://doi.org/10.3390/cells14030192

APA Style

Dahl-Wilkie, H., Gomez, J., Kelley, A., Manjit, K., Mansoor, B., Kanumuri, P., Pardo, S., Molleur, D., Falah, R., Konakalla, A. R., Omiyale, M., Weintraub, S., & Delk, N. A. (2025). Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response. Cells, 14(3), 192. https://doi.org/10.3390/cells14030192

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