Date of Award
2024
Document Type
Open Access Master's Thesis
Degree Name
Master of Science in Biological Sciences (MS)
Administrative Home Department
Department of Biological Sciences
Advisor 1
Xiaohu Tang
Committee Member 1
Zhiying Shan
Committee Member 2
Marina Tanasova
Abstract
Metabolic dysregulation, a critical hallmark of cancer, predisposes potential vulnerabilities for the development of targeted therapy. LKB1, a pivotal metabolic regulator and tumor suppressor, is often lost in many cancers. Our laboratory has unveiled that LKB1 suppresses phosphodiesterases (PDEs), and PDE3 modulators can selectively eradicate LKB1-deficient tumor cells. Through metabolic gene sgRNA library screening, Sarcolipin, an inhibitor of Sarcoendoplasmic Reticulum Calcium ATPase (SERCA), emerged as essential for cell death in this context. However, the precise molecular mechanisms by which PDE3 modulators exert their effects remain elusive. This study aims to uncover these mechanisms via RNA-Seq profiling and differential gene analysis, revealing that PDE3 modulators trigger significant ER stress and ribotoxic stress responses. Further exploration of various pathways through inhibitors and activators demonstrated that activation of SERCA mitigates stress responses and counteracts the cell death triggered by PDE3 modulators. Our findings help define a targeted therapy for cancers harboring LKB1 mutations.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.
Recommended Citation
Ahsan, Aqsa, "Exploring the Molecular Pathways of Cell Death Induced by PDE3 Modulators", Open Access Master's Thesis, Michigan Technological University, 2024.