The role of p62 in cell death and survival of 5-fluorouracil and oxaliplatin-resistant colorectal cancer cells

The role of p62 in cell death and survival of 5-fluorouracil and oxaliplatin-resistant colorectal cancer cells

The protein sequestosome 1 (p62/SQSTM1) is primarily known as a selective autophagy cargo receptor, but due to its multidomain structure, it also has roles in the ubiquitin-proteasome system, metabolism, cell death and survival signalling. The increase in p62 levels is detected in some types of canc...

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Bibliographic Details
Published in:Journal of cellular biochemistry Vol. 124; no. 11; pp. 1779 - 1791
Main Authors: Zitkute, Vilmante, Jasinevicius, Andrius, Vaitiekaite, Guoda, Kukcinaviciute, Egle, Aleksandraviciute, Bernadeta, Eidenaite, Eigile, Sudeikis, Lukas, Jonusiene, Violeta, Sasnauskiene, Ausra
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01-11-2023
Subjects:
5-Fluorouracil
Apoptosis
Autophagy
BAX protein
Bcl-2 protein
Cancer
Caspase
Cell Death
Cell Line, Tumor
Cell survival
Chemoresistance
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Down-regulation
Drug Resistance, Neoplasm
Fluorouracil - pharmacology
Gene Expression Regulation, Neoplastic
Humans
Interleukin-8 - metabolism
Metabolism
Mortality
Oxaliplatin
Oxaliplatin - pharmacology
p62 Protein
Proteasomes
Proteins
Survival
Ubiquitin
5-fluorouracil
chemoresistance
colorectal cancer
apoptosis
oxaliplatin
p62/SQSTM1
cytokines
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Summary:The protein sequestosome 1 (p62/SQSTM1) is primarily known as a selective autophagy cargo receptor, but due to its multidomain structure, it also has roles in the ubiquitin-proteasome system, metabolism, cell death and survival signalling. The increase in p62 levels is detected in some types of cancers, including colorectal cancer (CRC). Chemoresistance is the main cause of high mortality rates of CRC patients. Since p62 can regulate both cell survival and death, it is a potential modulator of chemoresistance. The impact of p62 on molecular causes of chemoresistance in CRC cells is insufficiently analysed. Therefore, we aimed to determine the impact of p62 on apoptosis, RIPK1-pRIPK3 axis, and IL-8 levels in chemoresistant CRC cells. Our data revealed that p62 levels are higher in the 5-fluorouracil (5-FU)-resistant HCT116/FU subline compared to the parental cell line. 5-FU and oxaliplatin (OxaPt) treatment decreased p62 protein levels and it correlated with chemoresistance of HCT116 and DLD1 cell lines. The silencing of p62 increased CRC cell sensitivity to 5-FU and OxaPt, hence p62 is one of the factors supporting chemoresistance. The downregulation of p62 reduced the activation of caspase-3 and the levels of RIPK1 and pRIPK3. Furthermore, p62 silencing decreased the BAX/BCL2 ratio in the HCT116/FU subline and did not change the levels of apoptosis. Instead, p62 silencing reduced the amount of IL-8 protein. Our results show that p62 impacts chemoresistance by stimulating prosurvival signalling.
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content type line 23
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.30488