Dissertation
P38 MAPK MEDIATES HIF-1Α STABILIZATION AND THE HYPOXIC RESPONSE IN LEIOMYOSARCOMA CELLS
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2025
DOI:
https://doi.org/10.7273/000007379
Abstract
Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma (STS) characterized by high metastatic potential, poor clinical outcomes, and limited therapeutic options. Hypoxia is a defining feature of LMS tumors, contributing to tumor progression, therapy resistance, and angiogenesis. Hypoxia-inducible factor 1 (HIF-1) is the master regulator of cellular adaptation to low oxygen conditions, promoting the expression of genes that drive angiogenesis, metabolism, and survival. However, the regulation of HIF-1α, the oxygen-sensitive subunit of HIF-1, in LMS is unexplored. The mitogen-activated protein kinase (MAPK) pathways, including p38 MAPK, ERK, and JNK, are key stress-responsive kinases that modulate various cellular processes, yet their roles in regulating HIF-1α in LMS have not been investigated. This study investigates the role of p38 MAPK signaling in modulating HIF-1α expression, transcriptional activity, and angiogenic potential in LMS cells. Using leiomyosarcoma cell lines (SK-LMS-1 and SK-UT-1) and primary uterine smooth muscle cells (HUtSMC), this study demonstrates that p38 MAPK is essential for HIF-1α protein stability and its downstream gene expression under hypoxia. Amongst the MAPKs, pharmacological inhibition of p38 MAPK significantly reduces HIF-1α protein levels. This regulatory role of p38 MAPK is also important for the expression of hypoxia-inducible genes VEGFA, BNIP3, and IGFBP3 and hypoxia-induced endothelial cell growth and micro-vessel development, revealing a critical role of p38 MAPK in hypoxia-driven angiogenesis. Further analysis showed that p38 MAPK inhibition accelerates HIF-1α degradation independently of proteasomal activity, indicating an alternative stabilization mechanism beyond traditional oxygen-dependent regulation. Moreover, this study identifies LMS subtype-specific differences in HIF-1α regulation, with SK-UT-1 cells exhibiting lower HIF-1α expression and reduced angiogenic response to hypoxia, suggesting that some LMS tumors may bypass HIF-1 signaling. These findings emphasize the heterogeneity of LMS tumors and highlight p38 MAPK as a potential therapeutic target for disrupting hypoxia-driven tumor progression. While p38 MAPK inhibitors have been explored in cancer therapy, their efficacy in LMS remains unknown. By elucidating the role of p38 MAPK in hypoxic adaptation and tumor angiogenesis, this study provides new insights into the molecular mechanisms driving LMS progression and offers potential therapeutic strategies for targeting hypoxia-driven tumor growth.
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Details
- Title
- P38 MAPK MEDIATES HIF-1Α STABILIZATION AND THE HYPOXIC RESPONSE IN LEIOMYOSARCOMA CELLS
- Creators
- Nuha Rahman Haque
- Contributors
- Eric A Shelden (Chair)Heather Koehler (Committee Member)Cynthia Cooper (Committee Member)James MacLean (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 100
- Identifiers
- 99901221152401842
- Language
- English
- Resource Type
- Dissertation