The anticancer drug Taxol interferes with cell division, leading to cell death. But some cancer cells have found a way to resist treatment.

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How cancer cells tip the Bim balance in their favor

24 May 2019

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

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).

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Ruan, W., Venkatachalam, G., Sobota, R. M., Chen, L., Wang L. C., et al. Resistance to anti-microtubule drug-induced cell death is determined by regulation of BimEL expression. Oncogene 38, 4352–4365 (2019). | article

About the Researcher

Uttam Surana

Research Director

Institute of Molecular and Cell Biology
Uttam Surana received a PhD degree in 1986 from the Department of Molecular and Cellular Biology at the University of Arizona, US. After research stints at the University of Cambridge, UK, and the Institute of Molecular Pathology in Vienna, Austria, Surana joined IMCB in 1992 where he is a Research Director. He is also an Adjunct Professor at A*STAR's Bioprocessing Technology Institute, the Department of Pharmacology, Yong Loo Lin School of Medicine, and the Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore. For his outstanding contributions to the understanding of control circuits that regulate cell division, Surana was awarded Singapore’s National Science Award in 2007.

This article was made for A*STAR Research by Wildtype Media Group