Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Ramia J. Salloom; Iman M. Ahmad; Maher Y. Abdalla

doi:10.3389/fonc.2024.1431362

Frontiers in Oncology (Jul 2024)

Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Ramia J. Salloom,
Iman M. Ahmad,
Maher Y. Abdalla

Affiliations

Ramia J. Salloom: Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
Iman M. Ahmad: Department of Clinical, Diagnostic, and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, NE, United States
Maher Y. Abdalla: Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States

DOI: https://doi.org/10.3389/fonc.2024.1431362
Journal volume & issue: Vol. 14

Abstract

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IntroductionChemotherapy, notably docetaxel (Doc), stands as the primary treatment for castration-resistant prostate cancer (CRPC). However, its efficacy is hindered by side effects and chemoresistance. Hypoxia in prostate cancer (PC) correlates with chemoresistance to Doc-induced apoptosis via Heme Oxygenase-1 (HO-1) modulation, a key enzyme in heme metabolism. This study investigated targeting heme degradation pathway via HO-1 inhibition to potentiate the therapeutic efficacy of Doc in PC.MethodsUtilizing diverse PC cell lines, we evaluated HO-1 inhibition alone and with Doc on viability, apoptosis, migration, and epithelial- to- mesenchymal transition (EMT) markers and elucidated the underlying mechanisms.ResultsHO-1 inhibition significantly reduced PC cell viability under hypoxic and normoxic conditions, enhancing Doc-induced apoptosis through interconnected mechanisms, including elevated reactive oxygen species (ROS) levels, glutathione cycle disruption, and modulation of Signal Transducer and Activator of Transcription 1 (STAT1) pathway. The interplay between STAT1 and HO-1 suggests its reliance on HO-1 activation. Additionally, a decrease in cell migration and downregulation of EMT markers (vimentin and snail) were observed, indicating attenuation of mesenchymal phenotype.DiscussionIn conclusion, the combination of HO-1 inhibition with Doc holds promise for improving therapeutic outcomes and advancing clinical management in PC.

Published in Frontiers in Oncology

ISSN: 2234-943X (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.frontiersin.org/journals/oncology/

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