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.