How Cancer Cells Tip the Bim Balance in Their Favor

Cancer cells evade Taxol-induced cell death by downregulating the expression of a protein known as BimEL.

Cancer cells, cilia development, air pollution, photonic devices, Micro-lens, mosquito-borne infections, Microbiota, bone repair, 3D printing, neurodegenerative disease, cancer treatments, biological research, sepsis, foot and mouth disease, cytometry, batteries, Influenza A virus, vascular diseases, New Cancer Drugs, RNA molecules, polymers, antimicrobial resistance, Aging White Blood Cells, microviscosity, Transplant Drug, Nanophotonics, photonics, Built-In Nanobulbs, cerebral cortex, cancer cells, nanowires, optoelectronic, solar energy, gold nanowires, Chikungunya virus, concrete, glaucoma, light-emitting diode, Proteomics, nanostructures, nickel catalyst, Ultrafast lasers, liver capsular macrophages, obesity, cancer, lignin polymer, liver capsular macrophages, Ultrafast lasers, monocyte cells, cancer treatments, antibody drug, gene mutations, quantum-entangled photons, gut microbes, skin aging, stroke, machine learning, Cloned tumors, cancer, Rare Skin Disease, terahertz lasers, silicon-nanostructure pixels, oral cancer, heart muscle cells, cancer, cancer stem cells, gastric cancer, microelectromechanical systems, data storage, silicon nanostructures, Drug delivery, cancer, muscle nuclei, Lithography, silicon nanostructures, Quantum matter, robust lattice structures, potassium ions, Photothermal therapy, Photonic devices, Optical Components, retina, allergy, immune cells, catalyst, Nanopositioning devices, mold templates, lung cancer, cytoskeletons, hepatitis b, cardiovascular disease, memory deficits, Photonics, pre-eclampsia treatment, hair loss, nanoparticles, mobile security, Fluid dynamics, MXene, Metal-assisted chemical etching, nanomedicine, Colorectal cancer, cancer therapy, liver inflammation, cancer treatment, Semiconductor lasers, zika virus, catalysts, stem cells, fetal immune system, genetic disease, liver cancer, cancer, liver cancer, RNA editing, obesity, Microcapsules, genetic disease, Piezoelectrics, cancer, magnesium alloy, Quantum materials, therapeutic antibodies, diabetes, 2D materials, lithium-ion batteries, obesity, lupus, surfactants, Sterilization, skin on chip, Magnetic Skyrmions, cyber-security, wound infections, human genetics, immune system, eczema, solar cells, Antimicrobials, joint disorder, genetics, cancer

Each time a cell divides, a tightly orchestrated dance of DNA and proteins takes place to ensure that each daughter cell contains the right amount of genetic material. A structure known as the mitotic spindle is assembled to capture the condensed chromosomes and partition them equally into the daughter cells.

Anti-microtubule drugs such as paclitaxel (trade name Taxol) and vincristine kill rapidly dividing cancer cells by altering the dynamics of the mitotic spindle, thereby stopping chromosomes from being properly partitioned into daughter cells. This eventually results in programmed cell death, or apoptosis, of the cancer cells.

In this study, A*STAR researchers led by Uttam Surana at the Institute of Molecular and Cell Biology (IMCB) identified a mechanism by which cancer cells evade apoptosis and become resistant to the treatment with anti-microtubule drugs. They first demonstrated that resistance to anti-microtubule drug treatment was not due to mitotic slippage—the process by which cells prematurely exit mitosis to avoid cell death—as generally believed. Rather, the cancer cells downregulate the expression of a protein called BimEL.

“Bim is an activator of apoptosis, and BimEL refers to the ‘extra-long’ isoform of the protein,” said Surana. Therefore, by downregulating BimEL expression, the signal to initiate apoptosis is weakened in cancer cells, allowing them to survive the treatment with anti-microtubule drugs.

The researchers next sought to identify how cancer cells downregulate BimEL expression. They showed that cancer cells target BimEL for destruction via the activity of cullin-RING ubiquitin ligases—proteins that add a molecular ‘throw away’ tag to cellular components. Alternatively, or simultaneously, cancer cells stall BimEL production by blocking the transcription of BimEL mRNA.

“Hence, Bim expression can be used as a biomarker to guide therapy—if a tumor does not show Bim expression, anti-microtubule drug treatment will not be of any benefit. Also, therapeutic agents that augment the expression of Bim would be desirable ‘companion drugs’ to induce cell death in cancer cells that are resistant to anti-microtubule drugs such as Taxol,” Surana explained.

In the future, Surana’s team is interested in detailing the fates adopted by cancer cells that have escaped anti-microtubule drug-induced cell death. “Understanding these mechanisms may further lead to strategies to induce cell death, in the subsequent division cycle, in cells that have initially escaped Taxol-induced mitotic death,” Surana said.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Bioprocessing Technology Institute (BTI).