Biology subjects

Katzenellenbogen, B. S.

Publications and source records attributed to Katzenellenbogen, B. S..

3 recordsLinked to original sources

bioRxiv2024

Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway

Despite significant improvements in the prognosis of Multiple Myeloma (MM), relapsed/refractory MM remains a major challenge. BCL2 inhibitor Venetoclax induced complete or very good partial responses in 6% of non-t(11;14) MM cases, compared to 27% in t(11;14) cases, when used as monotherapy in relapsed/refractory MM. Though Venetoclax was proposed to treat t(11;14) cases, the resistance became a concern. Furthermore, non-t(11;14) cases account for 80-85% of MM cases, which underscores the value of Venetoclax in non-t(11;14) MM. Here, we report a recently-invented small molecule inhibitor of FOXM1 NB73 synergizing with Venetoclax in killing MM cells. FOXM1, a critical forkhead box transcription factor in high-risk and relapsed/refractory MM, represents a promising therapeutic target of MM. We examined the mechanisms underlying the synergies of Venetoclax and NB73 using multi-omics and molecular and cellular biology tools in non-t(11;14) myeloma cell lines with high FOXM1 expression. NB73 induces immediate loss of FOXM1, decreases BCL2 expression, and increases Puma expression in myeloma cells. Venetoclax enhances NB73-induced FOXM1 ubiquitination and degradation. The NB73-Venetoclax combination abrogates the binding of FOXM1 to the promoters of genes in the MYC pathway, such as PLK1, MYC, CDC20, and CCNA2, leading to the repression of the transcription of these MYC pathway genes. The PLK1-specific inhibitor GSK461364 synergies with NB73 in suppressing myeloma cell growth. Therefore, NB73 synergizes with Venetoclax in killing myeloma cells. Conclusively, the NB73-Venetoclax combination abolishes FOXM1-mediated transcriptional activation of the MYC pathway, resulting in intensive apoptosis of myeloma cells without t(11;14) but with high FOXM1 expression. Statement of significanceThis study implicates that targeting FOXM1 will alleviate resistance to BCL2 inhibitor Venetoclax in non-t(11;14) myeloma cells expressing high FOXM1.

cancer biology↗

bioRxiv2024

Asymmetric Allostery in Estrogen Receptor-α Homodimers Drives Responses to the Ensemble of Estrogens in the Hormonal Milieu

The estrogen receptor- (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations --receptor conformational heterodimers--mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining binding of the same ligand in crystal structures of ER in the agonist versus antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist versus antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric versus dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing new modes for ligand-dependent regulation of ER activity. SignificanceThe estrogen receptor- (ER) regulates transcription in response to a hormonal milieu that includes low levels of estradiol, a variety of environmental estrogens, as well as ER antagonists such as breast cancer anti-hormonal therapies. While ER has been studied as a homodimer, the variety of ligand and receptor concentrations in different tissues means that the receptor can be occupied with two different ligands, with only one ligand in the dimer, or as a monomer. Here, we use X-ray crystallography and molecular dynamics simulations to reveal a new mode for ligand regulation of ER activity whereby sequence-identical homodimers can act as functional or conformational heterodimers having unique signaling characteristics, with ligand-selective allostery operating across the dimer interface integrating two different signaling outcomes.

biophysics↗

bioRxiv2021

Targeting metabolic adaptations in the breast cancer liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ER activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. ImplicationsOur findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

cancer biology↗