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Research

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Research ideas

To enhance paclitaxel, our approach is to specifically target the Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20) enzyme complex to try and delay anaphase entry without inducing a mitotic cell cycle arrest (Schuyler, et al, 2018; Schuyler and Chen, 2021).  We speculate that delaying anaphase entry in the presence of 10 nM paclitaxel, the clinically relevant amount, may decrease multipolar spindles in genomically stable healthy cells and increase multipolar spindle formation in genomically unstable cancer cells.  Levels of multipolar spindles induced by 10 nM paclitaxel have been observed to decrease from prophase to metaphase in genomically stable CAL-51 cells, and have also been observed to decrease from metaphase into anaphase in genomically stable CAL-51, RPE-1 and MCF-10A cells, while, by contrast, in genomically unstable cells, like MDA-MB-231 and HeLa cells, the levels of multipolar spindles have been observed to increase from metaphase into anaphase (Scribano, et al., 2021).  Healthy human cells have been selected to be genomically stable (Knouse, et al., 2014; Liu, et al., 2022), while cancer cells have been selected to be genomically unstable resulting in aneuploidy (Weaver and Cleveland, 2006).  Thus, in the presence of 10 nM paclitaxel, a delay in anaphase entry may give genomically stable cells more time to repair their spindles, while genomically unstable cells delayed in anaphase entry may display an increase in multipolar spindles in anaphase, which will promote cancer cell death.  

研究方向

​為了促進抗癌藥物太平洋紫杉醇的效果，我們的策略為標靶APC/C-CDC20酵素複合體嘗試延遲進入anaphase但不導致細胞週期arrest (Schuyler, et al, 2018; Schuyler and Chen, 2021)。我們推測在10nM臨床相關劑量的太平洋紫杉醇處理下延遲進入anaphase可能減少正常細胞(基因穩定)並增加癌細胞(基因不穩定)的多極性紡錘體形成。已知10nM太平洋紫杉醇造成基因穩定的CAL-51細胞株在prophase到metaphase過程多極性紡錘體減少；基因穩定的CAL-51, RPE-1和MCF-10A細胞株在metaphase到anaphase過程多極性紡錘體減少​。相對的，10nM太平洋紫杉醇對於基因不穩定的細胞株如MDA-MB-231和HeLa cells在metaphase到anaphase過程多極性紡錘體卻是增加的(Scribano, et al., 2021)。​在自然演化下，正常人類細胞具有穩定的基因 (Knouse, et al., 2014; Liu, et al., 2022)，癌細胞則多為基因不穩定的非整倍體(Weaver and Cleveland, 2006)。因此，若能在10nM太平洋紫杉醇的處理下進一步延遲進入anaphase，可能提供基因穩定細胞更多時間修復紡錘體，並造成基因不穩定的細胞在anaphase的多極性紡錘體增加，​進而引發癌細胞死亡。

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Reference

Knouse, KA, Wu, J, Whittaker, CA, Amon, A. (2014). Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A. Sep 16;111(37):13409-14. doi: 10.1073/pnas.1415287111. Epub 2014 Sep 2.

 

Liu, L, Chen, H, Sun, C, Zhang, J, Wang, J, Du, M, Li, J, Di, L, Shen, J, Geng, S, Pang ,Y, Luo, Y, Wu, C, Fu, Y, Zheng, Z, Wang, J, Huang Y. (2022). Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling. Genome Res. Jan;32(1):44-54. doi: 10.1101/gr.275453.121. Epub 2021 Dec 28.

 

Schuyler, SC, Wu, YO, Chen, HY, Ding, YS, Lin, CJ, Chu, YT, Chen, TC, Liao, L, Tsai, WW, Huang, A, Wang, LI, Liao, TW, Jhuo, JH, Cheng, V. (2018). Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison. PLoS One. Jun 8;13(6):e0198930. doi: 10.1371/journal.pone.0198930.

 

Schuyler, SC and Chen HY. (2021) Using budding yeast to identify molecules that block cancer cell ‘mitotic slippage’ only in the presence of mitotic poisons. Int. J. Mol. Sci. 22, 7985.

 

Scribano, CM, Wan, J, Esbona, K, Tucker, JB, Lasek, A, Zhou, AS, Zasadil, LM, Molini, R, Fitzgerald, J, Lager, AM, Laffin, JJ, Correia-Staudt, K, Wisinski, KB, Tevaarwerk, AJ, O'Regan, R, McGregor, SM, Fowler, AM, Chappell, RJ, Bugni, TS, Burkard, ME, Weaver, BA. (2021). Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med. Sep 8;13(610):eabd4811. doi: 10.1126/scitranslmed.abd4811. Epub 2021 Sep 8.

 

Weaver, BA and Cleveland, DW. (2006). Does aneuploidy cause cancer? Curr Opin Cell Biol. Dec;18(6):658-67. doi: 10.1016/j.ceb.2006.10.002. Epub 2006 Oct 12.

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