Biology subjects

Yang, T.-Y.

Publications and source records attributed to Yang, T.-Y..

3 recordsLinked to original sources

bioRxiv2025

mRNA and Protein Expression of Fetal Insulin Receptor in Breast Cancer Cell Lines

The insulin receptor (IR) is expressed in breast cancer cells and plays a role in regulating tumor biology. There are two IR isoforms generated from the same gene. Alternate splicing with exclusion or inclusion of exon 11accounts for the two isoforms. The exon 11 excluded isoform (IR-A) is expressed during fetal development while the full-length adult IR (IR-B) is the primary form expressed during adult life. This splice variant results in a 12 amino acid variation in peptide sequence. Breast cancer cells overexpress IR-A with an increased IR-A:IR-B ratio. Most of these data were obtained by examining mRNA expressions. In this work, we examined over 40 breast cancer cell lines and patient tumor samples for mRNA expression of the IR isoforms to show that most cells overexpressed IR-A compared to IR-B. Further we used mass spectrometry to demonstrate IR-A protein expression in the Du4475 cell line which has a high level of IR-A mRNA expression. To our knowledge, this is the first demonstration of IR-A protein expression. Thus, IR-A mRNA and protein expression demonstrate a potential role for this insulin receptor isoform in breast cancer biology.

cancer biology↗

bioRxiv2022

NRF2 activation induces NADH-reductive stress providing a metabolic vulnerability in lung cancer

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines--an effect that was completely rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

molecular biology↗

bioRxiv2018

Multi-omic profiling of TKI resistant K562 cells suggests metabolic reprogramming to promote cell survival

Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, \"off-target\" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profiling of these cell lines to describe mechanisms of resistance at the protein and gene expression level. We used whole transcriptome sequencing and SWATH-based data-independent acquisition mass spectrometry (DIA-MS), which does not require isotopic labels and provides quantitative measurements of proteins in a comprehensive, unbiased fashion. The proteomic and transcriptional data were correlated to generate an integrated understanding of the gene expression and protein alterations associated with TKI resistance. We defined mechanisms of resistance and two novel markers, CA1 and alpha-synuclein, that were common to all TKIs tested. Resistance to all of the TKIs was associated with oxidative stress responses, hypoxia signatures, and apparent metabolic reprogramming of the cells. Metabolite profiling and glucose-dependence experiments showed that resistant cells had routed their metabolism through glycolysis (particularly through the pentose phosphate pathway) and exhibited disruptions in mitochondrial metabolism. These experiments are the first to report a global, integrated proteomic, transcriptomic and metabolic analysis of TKI resistance. These data suggest that although the mechanisms are complex, targeting metabolic pathways along with TKI treatment may overcome pan-TKI resistance.\n\nKey PointsO_LIAlterations to metabolism are a common feature of target-mutation-independent resistance in CML cells across multiple clinically relevant TKIs.\nC_LIO_LICarbonic anhydrase 1 (CA1) and a-synuclein (SNCA) are novel markers of metabolic reprogramming in TKI resistant CML cells.\nC_LI

cancer biology↗