Abstract
LOX regulates cancer progression in a variety of human malignancies. It is overexpressed in aggressive cancers and higher expression of LOX is associated with higher cancer mortality. Here, we report a new function of LOX in mitosis. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3(Ser10)-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression, suggesting that LOX binds to stabilized microtubules. LOX knockdown leads to G2/M phase arrest; reduced p-H3(Ser10), cyclin B1, CDK1, and Aurora B. Moreover, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules. Our findings suggest that LOX has a role in cancer cell mitosis and may be targeted to enhance the activity of microtubule inhibitors for cancer therapy.
Highlights
Mitosis is a critical cell cycle phase, and its precise orchestration is necessary for the maintenance of chromosomal stability in cells [1]
We recently discovered that lysyl oxidase (LOX) was involved in anaplastic thyroid cancer (ATC) progression and metastasis, and higher expression of LOX was associated with lower survival rates in patients with differentiated thyroid cancer [11]
Because LOX has been associated with aggressive cancers and metastasis, it is important to characterize the intracellular functions of LOX
Summary
Mitosis is a critical cell cycle phase, and its precise orchestration is necessary for the maintenance of chromosomal stability in cells [1]. Several important proteins that coordinate the spindle formation and the chromosomes’ dynamics during mitosis have been discovered. The key proteins involved in G2/M transition, mitotic entry, mitotic spindle assembly, chromatin condensation and segregation, and the cleavage furrow and midbody during cytokinesis consist of CDC25C, CDK1, CDK 2, Aurora A (AURKA) and B (AURKB), and polo-like kinase 1 (PLK1) [2, 3]. Current cancer therapy focuses mainly on identifying novel targets crucial in cancer initiation and/or progression, such as proteins that coordinate several functions in the cell cycle. Targeting mitosis in cancer cells is widely exploited as a therapeutic strategy. Drugs that selectively inhibit mitotic progression by disrupting spindles and kinetochore functions, and restricting key mitotic regulatory proteins are currently in various stages of clinical trials. Inhibition of the main regulators of mitotic entry leads to either an arrest in G2 or prevents mitotic entry, or leads to cell death in mitosis, known as mitotic catastrophe as a consequence of failure to complete mitosis [4, 5]
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