NEK2 induces autophagy‐mediated bortezomib resistance by stabilizing Beclin‐1 in multiple myeloma

Xia, Jiliang; He, Yanjuan; Meng, Bin; Chen, Shilian; Zhang, Jingyu; Wu, Xuan; Zhu, Yinghong; Shen, Yi; Feng, Xiangling; Guan, Yongjun; Kuang, Chunmei; Guo, Jiaojiao; Lei, Qian; Wu, Yangbowen; An, Gang; Li, Guancheng; Qiu, Lugui; Zhan, Fenghuang; Zhou, Wen

doi:10.1002/1878-0261.12641

Cited by 73 publications

(68 citation statements)

References 47 publications

(62 reference statements)

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“…Autophagy is activated by the assembly of a complex of NEK2/USP7/Beclin-1 in MM cells. Indeed, treatment with a combination of the autophagy inhibitor chloroquine (CQ) and the chemotherapeutic bortezomib (BTZ) significantly prevents NEK2-induced drug resistance in MM cells [156]. The efficacy of fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance.…”

Section: The Pivotal Role Of Ulk In the Development Of Drug Resistancmentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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Section: The Pivotal Role Of Ulk In the Development Of Drug Resistancmentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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“…Although NEK2 expression is upregulated in various cancers, the regulation of its expression remains unclear. Studies have shown that USP7 deubiquitinates NEK2 and affects its stability 13 . We therefore examined whether USP7 deubiquitinated NEK2 and affected its function in PAs, and confirmed a specific interaction between USP7 and NEK2 in transiently transfected HEK293T cells using co-immunoprecipitation (Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

NEK2 regulates cellular proliferation and cabergoline sensitivity in pituitary adenomas

Jian¹,

Sun²,

Sun³

et al. 2021

J. Cancer

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Objective: To identify critical roles played by NEK2 in prolactinomas and to clarify the corresponding underlying mechanisms. Methods: We performed RNA-seq on MMQ cell lines treated with the dopamine receptor agonist cabergoline (CAB) to identify genes involved in prolactinoma progression and dopamine receptor-agonist (DA) sensitivity. NEK2 was then selected for further study. The expression of NEK2 was examined using quantitative real-time PCR, western immunoblotting, and immunohistochemistry - both in pituitary adenomas (PA) and in normal pituitary tissue. We used gain-of-function and loss-of-function assays to explore the biologic roles of NEK2 in cell growth in vivo and in vitro . Co-immunoprecipitation was also used to detect the binding between NEK2 and USP7. Results: Herein, we reported that NEK2 was upregulated in prolactinomas, particularly dopamine-resistant prolactinomas. NEK2 overexpression significantly promoted pituitary tumor GH3 and MMQ cell proliferation, and it impaired cellular sensitivity to CAB. Conversely, knockdown of NEK2 inhibited GH3 and MMQ cell growth, and sensitized the cells to CAB. Mechanistically, NEK2 regulated cell proliferation via the Wnt-signaling pathway; and in addition, we demonstrated that USP7 interacted with, deubiquitylated, and stabilized NEK2. Conclusions: Collectively, our results suggest that NEK2 might be a potential therapeutic target for prolactinoma.

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“…It can pass through the BBB and is widely used for the treatment of glioma 21 . However, long-term application is likely to induce acquired drug resistance, and drug resistance is still one of the problems that cannot be ignored in the treatment of tumors 22 . In high-throughput sequencing results, we found that hsa_circ_0110757 of Mcl-1 was overexpressed in TMZ-resistant glioma patient tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

Hsa_circ_0110757 upregulates ITGA1 to facilitate temozolomide resistance in glioma by suppressing hsa-miR-1298-5p

Liu

Chen

et al. 2021

Cell Death Dis

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Temozolomide (TMZ) is the internationally recognized and preferred drug for glioma chemotherapy treatment. However, TMZ resistance in glioma appears after long-term use and is an urgent problem that needs to be solved. Circular RNAs (circRNAs) are noncoding RNAs and play an important role in the pathogenesis and progression of tumors. Hsa_circ_0110757 was identified in TMZ-resistant glioma cells by high-throughput sequencing analysis and was derived from reverse splicing of myeloid cell leukemia-1 (Mcl-1) exons. The role of hsa_circ_0110757 in TMZ-resistant glioma was evaluated both in vitro and in vivo. It was found that hsa_circ_0110757 and ITGA1 are more highly expressed in TMZ-resistant glioma than in TMZ-sensitive glioma. The overexpression of hsa_circ_0110757 in glioma patients treated with TMZ was obviously associated with tumor invasion. This study indicates that hsa_circ_0110757 inhibits glioma cell apoptosis by sponging hsa-miR-1298-5p to promote ITGA1 expression. Thus, hsa_circ_0110757/hsa-miR-1298-5p/ITGA could be a potential therapeutic target for reversing the resistance of glioma to TMZ.

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NEK2 induces autophagy‐mediated bortezomib resistance by stabilizing Beclin‐1 in multiple myeloma

Cited by 73 publications

References 47 publications

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

NEK2 regulates cellular proliferation and cabergoline sensitivity in pituitary adenomas

Hsa_circ_0110757 upregulates ITGA1 to facilitate temozolomide resistance in glioma by suppressing hsa-miR-1298-5p

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