KIFC1 is a novel potential therapeutic target for breast cancer

Li, Yonghe; Lü, Wenyan; Chen, Dongquan; Boohaker, Rebecca J.; Zhai, Ling; Padmalayam, Indira; Wennerberg, Krister; Xu, Bo; Zhang, Wei

doi:10.1080/15384047.2015.1070980

Cited by 85 publications

(95 citation statements)

References 21 publications

(31 reference statements)

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“…For example, KIFC1 is upregulated in human breast cancer [19], whereas KIF2C is upregulated in esophageal squamous cell carcinoma and is associated with poor prognosis [22]. KIF14 expression is significantly increased in cervical tumor tissues, and its expression is positively associated with a high tumor stage, lymph node metastasis, and chemoresistance [23].…”

Section: Discussionmentioning

confidence: 99%

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

Qiao

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer is the leading cause of cancer-related deaths worldwide. The outcome of patients with non-small cell lung cancer remains poor; the 5-year survival rate for stage IV non-small cell lung cancer is only 1.0%. KIF15 is a tetrameric kinesin spindle motor that has been investigated for its regulation of mitosis. While the roles of kinesin motor proteins in the regulation of mitosis and their potentials as therapeutic targets in pancreatic cancer have been described previously, the role of KIF15 in lung cancer development remains unknown. Methods: Paired lung carcinoma specimens and matched adjacent normal tissues were used for protein analysis. Clinical data were obtained from medical records. We first examined KIF15 messenger RNA expression in The Cancer Genome Atlas database, and then determined KIF15 protein levels using immunohistochemistry and western blotting. Differences between the groups were analyzed using repeated measures analysis of variance. Overall survival was analyzed using the Kaplan–Meier method. Cell-cycle and proliferation assays were conducted using A549, NCI-H1299, and NCI-H226 cells. Results: KIF15 was significantly upregulated at both the messenger RNA and protein levels in human lung tumor tissues. In patients with lung adenocarcinoma, KIF15 expression was positively associated with disease stages; high KIF15 expression predicted a poor prognosis. KIF15 knockdown using short hairpin RNA in two human lung adenocarcinoma cell lines induced G1/S phase cell cycle arrest and inhibited cell growth, but there was no effect in human lung squamous cell carcinoma. Conclusion: Our findings show that KIF15 is involved in lung cancer carcinogenesis. KIF15 could therefore serve as a specific prognostic marker for patients with lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

Qiao

Chen

et al. 2018

Cell Physiol Biochem

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“…Kinesin like protein (KIFC1), a unique mitotic kinesin, has recently emerged as an new anti-cancer drug target (17). Increased centrosome number, or centrosome amplification, has been reported in a variety of human primary cancers and correlates with aneuploidy, chromosomal instability and tumorigenesis (18–22).…”

Section: Introductionmentioning

confidence: 99%

“…reported that KIFC1 is overexpressed in human breast cancers, and that KIFC1 overexpression correlates to increased aggressiveness and poorer clinical outcomes in breast cancer patients (26). Recently, we also demonstrated that KIFC1 expression is up-regulated in breast cancer, particularly in triple negative breast cancer (TNBC), and that KIFC1 is highly expressed in human breast cancer cell lines, but is undetectable in primary normal human mammary epithelial cells and weakly expressed in two human fibroblast lines (17). We further showed that KIFC1 silencing significantly reduced breast cancer cell viability (17).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we also demonstrated that KIFC1 expression is up-regulated in breast cancer, particularly in triple negative breast cancer (TNBC), and that KIFC1 is highly expressed in human breast cancer cell lines, but is undetectable in primary normal human mammary epithelial cells and weakly expressed in two human fibroblast lines (17). We further showed that KIFC1 silencing significantly reduced breast cancer cell viability (17). In the present studies, we identified a small molecule KIFC1 inhibitor, SR31527, through a high-throughput screening (HTS) campaign.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a novel inhibitor of kinesin-like protein KIFC1

Zhang

Zhai

Wang

et al. 2016

Biochemical Journal

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Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast to normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selectively killing of cancer cells. In the present study, we identified a small molecule KIFC1 inhibitor, SR31527, which inhibited microtubule-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 μM. By using bio-layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity (Kd = 25.4 nM). Our results from computational modeling and STD-NMR experiment suggested that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra-centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.

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“…Likewise, co-immunoprecipitation results of PJ34 and KIFC1 have yet to be reported. Due to the fact that the KIFC1 mRNA level is shown to be significantly diminished in various PJ34 treated breast cancer cell lines [110], we speculate that PJ34 might be transcriptionally suppressing the expression of KIFC1 given that PARP has been formerly reported to be a transcriptional regulator [111]. …”

Section: Chemotherapies Against Kifc1mentioning

confidence: 99%

KIFC1: a promising chemotherapy target for cancer treatment?

Xiao

Yang

2016

Oncotarget

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The kinesin motor KIFC1 has been suggested as a potential chemotherapy target due to its critical role in clustering of the multiple centrosomes found in cancer cells. In this regard, KIFC1 seems to be non-essential in normal somatic cells which usually possess only two centrosomes. Moreover, KIFC1 is also found to initiatively drive tumor malignancy and metastasis by stabilizing a certain degree of genetic instability, delaying cell cycle and protecting cancer cell surviving signals. However, that KIFC1 also plays roles in other specific cell types complicates the question of whether it is a promising chemotherapy target for cancer treatment. For example, KIFC1 is found functionally significant in vesicular and organelle trafficking, spermiogenesis, oocyte development, embryo gestation and double-strand DNA transportation. In this review we summarize a recent collection of information so as to provide a generalized picture of ideas and mechanisms against and in favor of KIFC1 as a chemotherapy target. And we also drew the conclusion that KIFC1 is a promising chemotherapy target for some types of cancers, because the side-effects of inhibiting KIFC1 mentioned in this review are theoretically easy to avoid, while KIFC1 is functionally indispensable during mitosis and malignancy of multi-centrosome cancer cells. Further investigations of how KIFC1 is regulated throughout the mitosis in cancer cells are needed for the understanding of the pathways where KIFC1 is involved and for further exploitation of indirect KIFC1 inhibitors.

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KIFC1 is a novel potential therapeutic target for breast cancer

Cited by 85 publications

References 21 publications

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

Discovery of a novel inhibitor of kinesin-like protein KIFC1

KIFC1: a promising chemotherapy target for cancer treatment?

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