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Spirobenin, A Small Chemical that Targets the Hec1/Nek2 Mitotic Pathway in Breast Cancers
Various defects in mitosis give rise to pleiomorphic effects on the cellular genome, often leading to severe instability, a hallmark of human cancers. To ensure faithful and efficient mitosis, multiple interrelated cellular pathways tightly regulate this process. While the defects in these pathways may cause mitotic failure, molecular intervention of the key regulators might serve as a platform to develop useful strategies for cancer therapy. We previously identified Hec1 as a critical mitotic regulator highly expressed in breast cancers as well as some other types of cancer cells. Hec1 physically and functionally interacts with the mitotic kinase Nek2 and is required for faithful chromosome segregation and efficient mitotic progress. The inactivation of Hec1 or Nek2 results in mitotic catastrophe and cell death. We have sought to recapitulate this event by screening small chemicals that can specifically disrupt the Hec1/Nek2 interaction, using a yeast-two-hybrid based assay system. One prominent compound identified (spirobenin) displays anti-cancer activity towards several breast cancer cells at low dose (10-300 nM). We hypothesize that spirobenin can induce mitotic dysfunction and cell death by targeting the Hec1/Nek2 complex. To address this, we propose first to validate the targeting efficiency and specificity of spirobenin both in vitro and in established cell lines; second, to investigate the underlying molecular basis by which spirobenin selectively inhibits the growth of a subset of breast cancers with extremely high-efficacy; and third assess the drugability both in terms of cytotoxicity and efficacy of this compound. We will use complementary approaches to determine whether spirobenin alters the binding specificity between Hec1 or Nek2. Additionally, we plan to examine the effects of spirobenin on several key mitotic pathways. In parallel, we will employ micro-array techniques to analyze the molecular profiles of breast cancer lines known to be highly sensitive to spirobenin. Finally, we will determine the cell-killing effect of spirobenin on a series of breast cancer cells and mouse tumor xenograft models. We expect that spirobenin will specifically interfere with the Hec1/Nek2 complex, compromising mitotic progression of living cells and resulting in cell death. Our work will, for the first time, provide a biological basis for the Hec1/Nek2 pathway as a molecular target for spirobenin to treat breast cancers.
Proper cell cycle controls are critical in maintaining cellular homeostasis, normal cell growth, and differentiation. To achieve cell growth, cells must divide (mitosis) to generate two daughter cells. Mitosis is accompanied by dramatic changes in cell morphology and intracellular organizations that are tightly controlled by a set of mitosis-associated activities. While defects in mitosis might cause mitotic failure, artificial intervention of the key mitotic regulators might help develop useful strategies for cancer therapy. Many chemicals (e.g., Taxol) inhibit cell growth by targeting the cellular machinery required for mitosis. However, the neuropathic side-effect posed by Taxol treatment has rendered the quest for alternative mitotic targets with higher specificity imperative. Previously, we identified Hec1 ( H ighly E xpressed in C ancers) as a molecule critical for mitosis. Hec1 controls mitotic progress in part by interacting with another mitotic regulator Nek2 that functions by phosphorylating downstream effectors. The phosphorylation of Hec1 by Nek2 is critical for proper mitotic control. The inactivation of Hec1 or Nek2 leads to mitotic failure and cell death. We have used the Hec1/Nek2 pathway as a target to screen for lead compounds that can specifically disrupt the Hec1/Nek2 interaction and have found that a candidate compound, named spirobenin, exhibits promising anti-cancer activity towards a subset of breast cancer cells. Here we propose biological studies to investigate the targeting specificity and the structural basis by which spirobenin inhibits Hec1/Nek2 complex formation, and to assess the anti-tumor efficacy of spirobenin in established breast cancer cells and mouse breast carcinoma xenograft models. We also plan to address why some subsets of breast cancers are extremely sensitive to spirobenin treatment. We will employ a set of multidisciplinary approaches to address our objectives, including biochemical, cell biological, structure biological and animal studies, which in the past we have successfully performed on another promising compound that targets a different cellular pathway, also in breast cancer models. By unraveling the biological mechanism of the Hec1/Nek2 interaction and elucidating key steps of intervention, it is our goal to establish and introduce spirobenin as a valuable and promising candidate for the development of an optimized therapeutic to specifically treat human breast cancers.