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Apr 27, 2011

Scientists Identify Dynein Subunit Protein as Potential Target for Ovarian Cancer

  • Researchers claim overexpression of the dynein subunit protein km23-1 effectively checks growth of human ovarian cancer tumor cells in vitro and also significantly reduces the tumorigenicity of human SKOV-3 cancer cells transplanted in mice. The scientists, led by Penn State College of Medicine’s Kathleen M. Mulder, Ph.D., and Nageswara Pulipati, Ph.D., are now working to see whether the effects of km23-1 overexpression could be mimicked as an approach to cancer therapy.

    Their research is published in the International Journal of Cancer in a paper titled “Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.”

    Dr. Mulder’s lab had previously shown that km23-1 is defective in approaching 50% of ovarian cancer patients. In their latest work they generated a tet-off inducible expression system in SKOV-3 cells in which the expression of km23-1 was induced upon doxycycline removal. They found that forced expression of km23-1 inhibited both anchorage-dependent and anchorage-independent growth of SKOV-3 cells and importantly, halted the growth of SKOV-3 tumors in mouse xenografts.

    Analyses of the cells suggested that km23-1 suppressed the ovarian cancer cells’ growth by inducing a mitotic delay, with immunofluorescence assays demonstrating that the cells were accumulating at prometaphase/metaphase. Significantly, although the mitotic spindle assembly checkpoint protein BubR1 was present in the cancer cells whether they overexpressed km23-1 or not, it was inappropriately retained at the metaphase kinetochore in km23-1-overexpressing  cells.

    “With the overexpression of km23-1, the checkpoint stays on and cell division does not proceed normally, which leads to a slow cell death,” Dr. Mulder explains. “Thus, the mechanism by which high levels of km23-1 suppress ovarian carcinoma growth in vitro and inhibit ovary tumor formation in vivo appears to involve a BubR1-related mitotic delay,” the authors conclude.


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