Cell Cycle最新文献

While the Warburg effect is well-known and frequently studied, the molecular features that facilitate increased tumor cell glycolytic activity have yet to be extensively investigated. We hypothesized that amplification of genes encoding proteins related to glucose metabolism could be a mechanism to facilitate increased glycolysis. Thus, we applied a precision-guided copy number variation analysis approach to the GLP1R, AMFR, GCG, GPI, and ACTA1 genes across three different cancer types. Results indicated that higher CNs of GLP1R in glioblastoma were associated with better patient outcomes, while high CNs of GPI in lower-grade gliomas were associated with worse outcomes. Results also indicated that high microsatellite instability directly correlated with high CNs for most of the above indicated genes. These approaches to assessing tumor metabolism-related genes may lead to more accurate measures of patient risk and potential additional treatment options.

Microtubules are polymers of α/β tubulin dimers that build the mitotic spindle, which segregates duplicated chromosomes during cell division. Microtubule function is governed by dynamic instability, whereby cycles of growth and shrinkage contribute to the forces necessary for chromosome movement. Regulation of microtubule growth velocity requires cell cycle-dependent changes in expression, localization and activity of microtubule-associated proteins (MAPs) as well as tubulin post-translational modifications that modulate microtubule dynamics. It has become clear that optimal microtubule growth velocities are required for proper chromosome segregation and ploidy maintenance. Suboptimal microtubule growth rates can result from altered activity of MAPs and could lead to aneuploidy, possibly by disrupting the establishment of microtubule bundles at kinetochores and altering the mechanical forces required for sister chromatid segregation. Future work using high-resolution, low-phototoxicity microscopy and novel fluorescent markers will be invaluable in obtaining deeper mechanistic insights into how microtubule processes contribute to chromosome segregation.

α-Fodrin, a known scaffolding protein for cytoskeleton stabilization, performs various functions including cell adhesion, cell motility, DNA repair and apoptosis. Based on our previous results revealing its role in mitosis in glioblastoma, we have examined its effect in pancreatic cancer, which is often linked to mitotic aberrations including aneuploidy and chromosome instability. Here, we show that the expression of α-Fodrin increases in pancreatic adenocarcinoma tissues compared to its normal counterpart, suggesting its tumor promoting role. shRNA-mediated knock-down of α-Fodrin significantly reduces the xenograft growth in immunocompromised mice underscoring the importance of α-Fodrin in tumor progression. CENP-E (centromere-associated protein E) is a motor protein essential for chromosomal alignment and segregation during mitosis. We have found that α-Fodrin interacts with CENP-E to recruit it to the kinetochore and depletion of α-Fodrin has a crucial role in controlling aneuploidy. As these mitotic defects can lead to apoptosis, we have further evaluated the activation of possible upstream pathways. Paclitaxel, a chemotherapeutic agent that stabilizes microtubules, disrupts mitosis and induces apoptosis. We found that Paclitaxel triggered stronger activation of JNK, ERK, and P38 MAPKs, altered BCL2/BAX ratios, cytochrome C release causing increased apoptosis in α-Fodrin knockdown cells compared to cells with wild-type α-Fodrin. This enhanced sensitivity to paclitaxel is consistent with improved survival in pancreatic cancer patients with low α-Fodrin (SPTAN1) and low CENP-E expression compared to poor prognosis with high expressions of both the genes. Taken together, this study provides the molecular mechanism by which α-Fodrin - CENP-E axis regulates pancreatic cancer progression and drug response.