cNEK6 induces gemcitabine resistance by promoting glycolysis in pancreatic ductal adenocarcinoma via the SNRPA/PPA2c/mTORC1 axis - Details

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Resistance　to　gemcitabine　in　pancreatic　ductal　adenocarcinoma　(PDAC)　leads　to　ineffective　chemotherapy　and,　consequently,　delayed　treatment,　thereby　contributing　to　poor　prognosis.　Glycolysis　is　an　important　intrinsic　reason　for　gemcitabine　resistance　as　it　competitively　inhibits　gemcitabine　activity　by　promoting　deoxycytidine　triphosphate　accumulation　in　PDAC.　However,　biomarkers　are　lacking　to　determine　which　patients　can　benefit　significantly　from　glycolysis　inhibition　under　the　treatment　of　gemcitabine　activity,　and　a　comprehensive　understanding　of　the　molecular　mechanisms　that　promote　glycolysis　in　PDAC　will　contribute　to　the　development　of　a　strategy　to　sensitize　gemcitabine　chemotherapy.　In　this　study,　we　aimed　to　identify　a　biomarker　that　can　robustly　indicate　the　intrinsic　resistance　of　PDAC　to　gemcitabine　and　guide　chemotherapy　sensitization　strategies.　After　establishing　gemcitabine-resistant　cell　lines　in　our　laboratory　and　collecting　pancreatic　cancer　and　adjacent　normal　tissues　from　gemcitabine-treated　patients,　we　observed　that　circRNA　hsa_circ_0008383　(namely　cNEK6)　was　highly　expressed　in　the　peripheral　blood　and　tumor　tissues　of　patients　and　xenografts　with　gemcitabine-resistant　PDAC.　cNEK6　enhanced　resistance　to　gemcitabine　by　promoting　glycolysis　in　PDAC.　Specifically,　cNEK6　prevented　K48　ubiquitination　of　small　ribonucleoprotein　peptide　A　from　the　BTRC,　a　ubiquitin　E3　ligase;　thus,　the　accumulated　SNRPA　stopped　PP2Ac　translation　by　binding　to　its　G-quadruplexes　in　5′　UTR　of　mRNA.　mTORC1　pathway　was　aberrantly　phosphorylated　and　activated　owing　to　the　absence　of　PP2Ac.　The　expression　level　of　cNEK6　in　the　peripheral　blood　and　tumor　tissues　correlated　significantly　and　positively　with　the　activation　of　the　mTORC1　pathway　and　degree　of　glycolysis.　Hence,　the　therapeutic　effect　of　gemcitabine　is　limited　in　patients　with　high　cNEK6　levels,　and　in　combination　with　the　mTORC1　inhibitor,　rapamycin,　can　enhance　sensitivity　to　gemcitabine　chemotherapy.　(Figure　presented.)　©　The　Author(s)　2024.

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[ 1 ] [Li G.]Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
[ 2 ] [Li G.]Fujian Medical University Cancer Center, Fuzhou, China
[ 3 ] [Li G.]Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
[ 4 ] [Li G.]Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
[ 5 ] [She F.-F.]Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
[ 6 ] [She F.-F.]Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
[ 7 ] [Liao C.-Y.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 8 ] [Liao C.-Y.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 9 ] [Liao C.-Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 10 ] [Wang Z.-W.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 11 ] [Wang Z.-W.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 12 ] [Wang Z.-W.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 13 ] [Wang Y.-T.]Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China
[ 14 ] [Wu Y.-D.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 15 ] [Wu Y.-D.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 16 ] [Wu Y.-D.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 17 ] [Huang X.-X.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 18 ] [Huang X.-X.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 19 ] [Huang X.-X.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 20 ] [Xie C.-K.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 21 ] [Xie C.-K.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 22 ] [Xie C.-K.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 23 ] [Lin H.-Y.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 24 ] [Lin H.-Y.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 25 ] [Lin H.-Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 26 ] [Zhu S.-C.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 27 ] [Zhu S.-C.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 28 ] [Zhu S.-C.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 29 ] [Chen Y.-H.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 30 ] [Chen Y.-H.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 31 ] [Chen Y.-H.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 32 ] [Wu Z.-H.]Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
[ 33 ] [Wu Z.-H.]Fujian Medical University Cancer Center, Fuzhou, China
[ 34 ] [Wu Z.-H.]Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
[ 35 ] [Wu Z.-H.]Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
[ 36 ] [Chen J.-Z.]Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
[ 37 ] [Chen J.-Z.]Fujian Medical University Cancer Center, Fuzhou, China
[ 38 ] [Chen J.-Z.]Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
[ 39 ] [Chen J.-Z.]Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
[ 40 ] [Chen S.]Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
[ 41 ] [Chen S.]Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, China
[ 42 ] [Chen S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
[ 43 ] [Chen Y.-L.]Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
[ 44 ] [Chen Y.-L.]Fujian Medical University Cancer Center, Fuzhou, China
[ 45 ] [Chen Y.-L.]Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
[ 46 ] [Chen Y.-L.]Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China

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Cell Death and Disease

ISSN： 2041-4889

Year： 2024

Issue： 10

Volume： 15

8 . 1 0 0

JCR@2023

CAS Journal Grade：2

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