PMID- 34726248
OWN - NLM
STAT- MEDLINE
DCOM- 20220308
LR  - 20220308
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 59
IP  - 6
DP  - 2021 Dec
TI  - Shikonin suppresses colon cancer cell growth and exerts synergistic effects by 
      regulating ADAM17 and the IL‑6/STAT3 signaling pathway.
LID - 99 [pii]
LID - 10.3892/ijo.2021.5279 [doi]
AB  - Signal transducer and activator of transcription 3 (STAT3) activation is 
      associated with drug resistance induced by anti‑epidermal growth factor receptor 
      (anti‑EGFR) therapy in the treatment of colon cancer. Thus, the combined 
      inhibition of EGFR and STAT3 may prove beneficial for this type of cancer. STAT3 
      has been proven to play a critical role in colon cancer initiation and 
      progression, and is considered the primary downstream effector driven by 
      interleukin‑6 (IL‑6). A disintegrin and metalloproteinase 17 (ADAM17), documented 
      as an oncogene, catalyzes the cleavage of both EGF and IL‑6R, inducing EGFR 
      signaling and enabling IL‑6 trans‑signaling to activate STAT3 in a wide range of 
      cell types to promote inflammation and cancer development. As a natural product, 
      shikonin (SKN) has been found to function as an antitumor agent; however, its 
      role in the regulation of ADAM17 and IL‑6/STAT3 signaling in colon cancer cells 
      remains unknown. In the present study, it was found that SKN inhibited colon 
      cancer cell growth, suppressed both constitutive and IL‑6‑induced STAT3 
      phosphorylation, and downregulated the expression of ADAM17. ADAM17 expression 
      was not altered in response to STAT3 knockdown, while IL‑6‑induced STAT3 
      activation did not induce ADAM17 transcripts. Furthermore, it was demonstrated 
      that SKN did not affect the expression of key proteins involved in the maturation 
      and degradation of ADAM17. SKN decreased ADAM17 expression possibly through 
      reactive oxygen species (ROS)‑mediated translational inhibition, as evidenced by 
      the increased ADAM17 mRNA and phosphorylation levels of eukaryotic initiation 
      factor 2alpha (eIF2alpha). The expression of ADAM17 and p‑eIF2alpha was reversed by 
      N‑acetylcysteine (NAC, a ROS scavenger). Taken together, these results indicate 
      that the concurrent inhibition of ADAM17 and IL‑6/STAT3 signaling by SKN may 
      synergistically contribute to the suppression of colon cancer cell growth.
FAU - Shi, Wei
AU  - Shi W
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Men, Lintong
AU  - Men L
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Pi, Xiu
AU  - Pi X
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Jiang, Tao
AU  - Jiang T
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Peng, Dewei
AU  - Peng D
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Huo, Shengqi
AU  - Huo S
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Luo, Pengcheng
AU  - Luo P
AD  - Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
FAU - Wang, Moran
AU  - Wang M
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Guo, Junyi
AU  - Guo J
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Jiang, Yue
AU  - Jiang Y
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Peng, Lulu
AU  - Peng L
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Lin, Li
AU  - Lin L
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Li, Sheng
AU  - Li S
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
FAU - Lv, Jiagao
AU  - Lv J
AD  - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 
      430030, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20211102
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Naphthoquinones)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 3IK6592UBW (shikonin)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
SB  - IM
MH  - ADAM17 Protein/genetics/*metabolism
MH  - Anti-Inflammatory Agents, Non-Steroidal/pharmacology
MH  - Apoptosis
MH  - Cell Proliferation
MH  - Colonic Neoplasms/*drug therapy/metabolism/pathology
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Interleukin-6/genetics/*metabolism
MH  - Naphthoquinones/*pharmacology
MH  - STAT3 Transcription Factor/genetics/*metabolism
MH  - Tumor Cells, Cultured
PMC - PMC8577797
OTO - NOTNLM
OT  - A disintegrin and metalloproteinase 17
OT  - IL‑6
OT  - STAT3
OT  - colon cancer
OT  - shikonin
COIS- The authors declare that they have no competing interests.
EDAT- 2021/11/03 06:00
MHDA- 2022/03/09 06:00
PMCR- 2021/11/01
CRDT- 2021/11/02 09:14
PHST- 2020/12/17 00:00 [received]
PHST- 2021/07/20 00:00 [accepted]
PHST- 2021/11/02 09:14 [entrez]
PHST- 2021/11/03 06:00 [pubmed]
PHST- 2022/03/09 06:00 [medline]
PHST- 2021/11/01 00:00 [pmc-release]
AID - 99 [pii]
AID - ijo-59-06-05279 [pii]
AID - 10.3892/ijo.2021.5279 [doi]
PST - ppublish
SO  - Int J Oncol. 2021 Dec;59(6):99. doi: 10.3892/ijo.2021.5279. Epub 2021 Nov 2.