TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ
Identifieur interne : 000402 ( Main/Curation ); précédent : 000401; suivant : 000403TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ
Auteurs : Hui Lu ; Juanjuan Xiao ; Changshu Ke ; Xiaofang Ni ; Ruijuan Xiu ; Qin Tian ; Huaxiong Pan ; Ling Zou ; Fei Wang ; Tengfei Ma ; Xinying Ji ; Ping Yuan ; Lin Liu ; Jianmin Zhang ; Wei Jia ; Qiuhong Duan ; Feng ZhuSource :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.
Url:
DOI: 10.1038/s41419-019-1805-9
PubMed: 31378785
PubMed Central: 6680050
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<author><name sortKey="Xiao, Juanjuan" sort="Xiao, Juanjuan" uniqKey="Xiao J" first="Juanjuan" last="Xiao">Juanjuan Xiao</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Pathology, Tongji Hospital, Tongji Medical College,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
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<author><name sortKey="Ni, Xiaofang" sort="Ni, Xiaofang" uniqKey="Ni X" first="Xiaofang" last="Ni">Xiaofang Ni</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
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</author>
<author><name sortKey="Xiu, Ruijuan" sort="Xiu, Ruijuan" uniqKey="Xiu R" first="Ruijuan" last="Xiu">Ruijuan Xiu</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
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<author><name sortKey="Tian, Qin" sort="Tian, Qin" uniqKey="Tian Q" first="Qin" last="Tian">Qin Tian</name>
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430030 Wuhan, Hubei PR China</nlm:aff>
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<institution>Department of Pathology, Union Hospital,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
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430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
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<author><name sortKey="Ma, Tengfei" sort="Ma, Tengfei" uniqKey="Ma T" first="Tengfei" last="Ma">Tengfei Ma</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ji, Xinying" sort="Ji, Xinying" uniqKey="Ji X" first="Xinying" last="Ji">Xinying Ji</name>
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<institution-id institution-id-type="GRID">grid.256922.8</institution-id>
<institution>Henan International Joint Laboratory of Nuclear Protein Regulation,</institution>
<institution>Henan University Medical Center (HUMC),</institution>
</institution-wrap>
475004 Kaifeng, Henan PR China</nlm:aff>
<wicri:noCountry code="subfield">Henan PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yuan, Ping" sort="Yuan, Ping" uniqKey="Yuan P" first="Ping" last="Yuan">Ping Yuan</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Liu, Lin" sort="Liu, Lin" uniqKey="Liu L" first="Lin" last="Liu">Lin Liu</name>
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<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Jia, Wei" sort="Jia, Wei" uniqKey="Jia W" first="Wei" last="Jia">Wei Jia</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Duan, Qiuhong" sort="Duan, Qiuhong" uniqKey="Duan Q" first="Qiuhong" last="Duan">Qiuhong Duan</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhu, Feng" sort="Zhu, Feng" uniqKey="Zhu F" first="Feng" last="Zhu">Feng Zhu</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Biochemistry and Molecular Biology, School of Basic Medicine,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
430030 Wuhan, Hubei PR China</nlm:aff>
<wicri:noCountry code="subfield">Hubei PR China</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p id="Par1">ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.</p>
</div>
</front>
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