NEK2 Induces Drug Resistance Mainly through Activation of Efflux Drug Pumps and Is Associated with Poor Prognosis in Myeloma and Other Cancers

Zhou, Wen; Yang, Ye; Xia, Jiliang; Wang, He; Salama, Mohamed E.; Wang, Xiong; Xu, Hui; Shetty, Shashirekha; Chen, Tiehua; Zeng, Zhaoyang; Shi, Lei; Zangari, Maurizio; Miles, Rodney R.; Bearss, David J.; Tricot, Guido; Zhan, Fenghuang

doi:10.1016/j.ccr.2012.12.001

Cited by 247 publications

(412 citation statements)

References 48 publications

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“…Viridin analogs, which are highly specific inhibitors of Nek2, can induce centrosome disruption and inhibit cancer cell growth in vitro (40). Other recent work has indicated that Nek2 silencing can induce apoptosis of cells that show chromosomal instability but not of cells with a normal karyotype (41,42). Our study provides in vivo validation of the concept that Nek2 is important for tumor growth in both primary and secondary sites, and strengthens the rationale underlying the growing efforts to develop specific therapeutic inhibitors against this kinase.…”

Section: Discussionmentioning

confidence: 99%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells in which a selected gene was stably knocked down were injected into the tail veins of mice and the formation of tumors in the lungs was monitored. One of several genes found to be important for tumor growth in lungs was Nek2, a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad.In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 plays a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

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Section: Discussionmentioning

confidence: 99%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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“…XIA LIU More recently, NEK2 has become important since two studies indicate that high expression of NEK2 induces drug resistance in multiple myeloma (21,22). However, despite these study, the research on NEK2 in regards to drug resistance in cancers is still limited, and its relationship with drug resistance in ovarian cancer has never been reported.…”

Section: Upregulation Of Nek2 Is Associated With Drug Resistance In Omentioning

confidence: 99%

“…The target gene, NEK2, which is closely associated with drug resistance in multiple myeloma (21,22) was selected for bioinformatic analysis. …”

Section: Methodsmentioning

confidence: 99%

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

et al. 2013

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Abstract. NEK2 [NIMA (never in mitosis gene A)-related expressed kinase 2] is associated with various biological behaviors in the development of cancer, while research concerning its association with drug resistance is limited. The association of NEK2 with drug resistance in ovarian cancer has not yet been reported. In the present study, on the basis of microarray results from Oncomine and the GEO Profiles online database, we revealed that NEK2 mRNA expression in ovarian cancer tissues is upregulated. In addition, its expression in drugresistant ovarian cancer cells was upregulated when compared with expression with their sensitive or parental counterparts. Finally, we performed a comprehensive bioinformatic analysis consisting of protein/gene-protein/gene interaction network, annotation of biological processes and microRNA-mRNA interaction analysis. We observed that NEK2 directly or indirectly interacts with a number of genes, proteins, microRNAs and biological processes associated with drug resistance in ovarian and other types of cancer. These results indicate that NEK2 contributes to drug resistance in ovarian cancer and it may be an important therapeutic target.

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“…9,[24][25][26] The details were described in the supplemental Data (available on the Blood Web site).…”

Section: Methodsmentioning

confidence: 99%

“…24 Briefly, 10 000 MM cells were seeded in 0.33% agar cultures. The colonies were fed with medium in the presence or absence of drugs; after 3 weeks, the plates were imaged and colony numbers were counted by ImageJ.…”

Section: Clonogenic Formation Assaymentioning

confidence: 99%

RARα2 expression confers myeloma stem cell features

Yang

Shi

Tolomelli

et al. 2013

Blood

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Key Points• RARa2 activates Wnt and hedgehog pathways in maintaining myeloma stem cell features and drug resistance.We previously demonstrated that RARa2 expression is increased in CD138 selected plasma cells of relapsed multiple myelomas (MMs), and increased expression was linked to poor prognosis in newly diagnosed MM patients. In the present study, we demonstrate that increased RARa2 confers myeloma stem cell features. Higher expression of RARa2 was identified in the multiple myeloma stem cell (MMSC) fraction. Overexpression of RARa2 in bulk MM cell lines resulted in: 1) increased drug resistance; 2) increased clonogenic potential; 3) activation of both Wnt and Hedgehog (Hh) pathways; 4) increased side population and aldehyde dehydrogenase levels; and 5) increased expression of embryonic stem cell genes. The opposite effects were seen with RARa2 knockdown. We demonstrate that RARa2 induces drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARa2 overexpressing MM cells. We also showed that in the 5TGM1 mouse model, targeting of the Wnt and Hh pathways using CAY10404, cyclopamine, or itraconazole significantly reduced the myeloma tumor burden and increased survival. Targeting RARa2 or its downstream signaling pathways provides a potential strategy to eliminate

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NEK2 Induces Drug Resistance Mainly through Activation of Efflux Drug Pumps and Is Associated with Poor Prognosis in Myeloma and Other Cancers

Cited by 247 publications

References 48 publications

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

RARα2 expression confers myeloma stem cell features

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