PMID- 29191829
OWN - NLM
STAT- MEDLINE
DCOM- 20181126
LR  - 20240102
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 3
DP  - 2018 Jan 19
TI  - ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal 
      adenocarcinoma by abrogating gemcitabine-mediated DNA damage.
PG  - 984-994
LID - 10.1074/jbc.M117.808584 [doi]
AB  - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor 
      prognosis. Gemcitabine, as a single agent or in combination therapy, remains the 
      frontline chemotherapy despite its limited efficacy due to de novo or acquired 
      chemoresistance. There is an acute need to decipher mechanisms underlying 
      chemoresistance and identify new targets to improve patient outcomes. Here, we 
      report a novel role for the ST6Gal-I sialyltransferase in gemcitabine resistance. 
      Utilizing MiaPaCa-2 and BxPC-3 PDAC cells, we found that knockdown (KD) of 
      ST6Gal-I expression, as well as removal of surface alpha2-6 sialic acids by 
      neuraminidase, enhances gemcitabine-mediated cell death assessed via clonogenic 
      assays and cleaved caspase 3 expression. Additionally, KD of ST6Gal-I potentiates 
      gemcitabine-induced DNA damage as measured by comet assays and quantification of 
      gammaH2AX foci. ST6Gal-I KD also alters mRNA expression of key gemcitabine metabolic 
      genes, RRM1, RRM2, hENT1, and DCK, leading to an increased gemcitabine 
      sensitivity ratio, an indicator of gemcitabine toxicity. Gemcitabine-resistant 
      MiaPaCa-2 cells display higher ST6Gal-I levels than treatment-naive cells along 
      with a reduced gemcitabine sensitivity ratio, suggesting that chronic 
      chemotherapy selects for clonal variants with more abundant ST6Gal-I. Finally, we 
      examined Suit2 PDAC cells and Suit2 derivatives with enhanced metastatic 
      potential. Intriguingly, three metastatic and chemoresistant subclones, S2-CP9, 
      S2-LM7AA, and S2-013, exhibit up-regulated ST6Gal-I relative to parental Suit2 
      cells. ST6Gal-I KD in S2-013 cells increases gemcitabine-mediated DNA damage, 
      indicating that suppressing ST6Gal-I activity sensitizes inherently resistant 
      cells to gemcitabine. Together, these findings place ST6Gal-I as a critical 
      player in imparting gemcitabine resistance and as a potential target to restore 
      PDAC chemoresponse.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Chakraborty, Asmi
AU  - Chakraborty A
AD  - From the Departments of Cell Developmental and Integrative Biology and.
FAU - Dorsett, Kaitlyn A
AU  - Dorsett KA
AD  - From the Departments of Cell Developmental and Integrative Biology and.
FAU - Trummell, Hoa Q
AU  - Trummell HQ
AD  - Radiation Oncology, University of Alabama, Birmingham, Alabama 35294.
FAU - Yang, Eddy S
AU  - Yang ES
AD  - Radiation Oncology, University of Alabama, Birmingham, Alabama 35294.
FAU - Oliver, Patsy G
AU  - Oliver PG
AD  - Radiation Oncology, University of Alabama, Birmingham, Alabama 35294.
FAU - Bonner, James A
AU  - Bonner JA
AD  - Radiation Oncology, University of Alabama, Birmingham, Alabama 35294.
FAU - Buchsbaum, Donald J
AU  - Buchsbaum DJ
AD  - Radiation Oncology, University of Alabama, Birmingham, Alabama 35294.
FAU - Bellis, Susan L
AU  - Bellis SL
AD  - From the Departments of Cell Developmental and Integrative Biology and 
      bellis@uab.edu.
LA  - eng
GR  - P30 AI027767/AI/NIAID NIH HHS/United States
GR  - P30 CA013148/CA/NCI NIH HHS/United States
GR  - R21 CA192629/CA/NCI NIH HHS/United States
GR  - P30 AR048311/AR/NIAMS NIH HHS/United States
GR  - R01 GM111093/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171130
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Equilibrative Nucleoside Transporter 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (SLC29A1 protein, human)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 1.17.4.- (ribonucleotide reductase M2)
RN  - EC 1.17.4.1 (RRM1 protein, human)
RN  - EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
RN  - EC 2.4.99.- (Sialyltransferases)
RN  - EC 3.2.1.18 (Neuraminidase)
RN  - EC 2.4.99.1 (beta-D-Galactoside alpha 2-6-Sialyltransferase)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Cell Line, Tumor
MH  - Comet Assay
MH  - DNA Damage/*drug effects/genetics
MH  - Deoxycytidine/*analogs & derivatives/pharmacology
MH  - Drug Resistance, Neoplasm/genetics
MH  - Equilibrative Nucleoside Transporter 1/genetics
MH  - Humans
MH  - Immunoblotting
MH  - Neuraminidase/metabolism
MH  - Pancreatic Neoplasms/*genetics
MH  - RNA, Messenger/genetics
MH  - Ribonucleoside Diphosphate Reductase/genetics
MH  - Sialyltransferases/genetics/*metabolism
MH  - Tumor Suppressor Proteins/genetics
MH  - beta-D-Galactoside alpha 2-6-Sialyltransferase
MH  - Gemcitabine
PMC - PMC5777269
OTO - NOTNLM
OT  - H2A histone family
OT  - chemoresistance
OT  - drug metabolism
OT  - gemcitabine
OT  - glycosylation
OT  - member X (H2AFX)
OT  - pancreatic cancer
OT  - pancreatic ductal adenocarcinoma (PDAC)
OT  - beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1)
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2017/12/02 06:00
MHDA- 2018/11/27 06:00
PMCR- 2017/11/30
CRDT- 2017/12/02 06:00
PHST- 2017/07/25 00:00 [received]
PHST- 2017/11/14 00:00 [revised]
PHST- 2017/12/02 06:00 [pubmed]
PHST- 2018/11/27 06:00 [medline]
PHST- 2017/12/02 06:00 [entrez]
PHST- 2017/11/30 00:00 [pmc-release]
AID - S0021-9258(20)39670-8 [pii]
AID - M117.808584 [pii]
AID - 10.1074/jbc.M117.808584 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Jan 19;293(3):984-994. doi: 10.1074/jbc.M117.808584. Epub 2017 
      Nov 30.