Date of Award
2024
Document Type
Campus Access Dissertation
Degree Name
Doctor of Philosophy in Biological Sciences (PhD)
Administrative Home Department
Department of Biological Sciences
Advisor 1
Mark Tang
Committee Member 1
Xiaoqing Tang
Committee Member 2
Rupali Datta
Committee Member 3
Smitha Rao
Abstract
Cancer heterogeneity significantly impacts treatment efficacy, underscoring the urgent need for personalized therapies tailored to the genetic and molecular differences of individual patients. Among various strategies, targeting metabolic deregulation—a hallmark of cancer often linked to oncogenic alterations—offers a promising avenue. This approach is particularly relevant in the context of Liver Kinase B1 (LKB1), a crucial player in cellular metabolism and tumor suppression, which is frequently mutated in cancers. Mutations in LKB1 are associated with accelerated tumor progression and adverse clinical outcomes, highlighting the necessity for targeted therapeutic strategies.
Our research unveils a novel aspect of LKB1's function in regulating cyclic nucleotide metabolism, specifically its role in suppressing a set of phosphodiesterase (PDE) expressions. Particularly, LKB1 represses PDE3 through the activation of downstream salt-inducible kinase (SIK). Furthermore, PDE3 modulators can selectively target LKB1-deficient tumor cells, in contrast to those with intact LKB1. In addition, we identify resistance in some LKB1-deficient cells due to the loss of SLFN12, a critical factor for PDE3 modulator-induced cell death. This resistance can be overcome by reactivation of SLFN12 expression with epigenetic inhibitors or cAMP inducers.
To further understand the mechanisms behind PDE3-modulator-induced cell death, we utilized a CRISPR/Cas9 small guide RNA (sgRNA) library screening approach targeting all metabolic genes in HeLa cells. We identified sarcolipin (SLN) as a crucial factor, finding that the loss of SLN significantly prevents cells from death. Given SLN's role in negatively regulating the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA), a SERCA activator demonstrated a protective effect in HeLa SLN wild-type cells by reducing calcium uptake into the endoplasmic reticulum. These results indicate a complex protein interaction network, including PDE3/SLFN12 and SERCA/SLN complexes, plays a role in cell death induced by PDE3 modulators.
Recommended Citation
Rono, Catherine, "Identifying and Exploiting Metabolic Vulnerabilities to Target LKB1-Mutant Cancers", Campus Access Dissertation, Michigan Technological University, 2024.