Highlights
- •Chemoresistance is the reason for the limited efficacy of breast cancer therapeutics.
- •Receptor activator of nuclear factor-kappa B ligand (RANKL) mediates chemoresistance in breast cancer cells through autophagy induction.
- •RANKL induces autophagy by activating the Janus protein tyrosine kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway.
- •Targeting RANKL/receptor activator of nuclear factor-kappa B (RANK) may be a potential strategy to overcome chemoresistance in breast cancer patients.
Abstract
Background
This study was to investigate the functional role and mechanism of receptor activator
of nuclear factor-kappa B ligand (RANKL) associated autophagy and chemoresistance
in breast cancer.
Materials and Methods
Cell Counting Kit-8 (CCK-8) assay was used to detect the cell viability. Real-time
polymerase chain reaction (PCR) was used for determining the relative mRNA levels
of key genes and protein expression was assessed by Western blotting. Immunofluorescence
was performed to evaluate the changes in the autophagy flux. Short hairpin (shRNA)
was used to knockdown the expression of the target genes in breast cancer cells. Based
on The Cancer Genome Atlas (TCGA) database, we explored the expression of receptor
activator of nuclear factor-kappa B (RANK), autophagy and signal transducer and activator
of transcription 3 (STAT3) signaling associated genes and analyzed their correlation
with the prognosis of breast cancer patients.
Results
The findings showed that receptor activator of nuclear factor-kappa B ligand (RANKL),
the ligand of RANK, could effectively enhance the chemoresistance potential of breast
cancer cells. Our results showed that RANKL induced autophagy and enhanced the expression
of autophagy associated genes in breast cancer cells. The knockdown of RANK suppressed
RANKL mediated autophagy induction in these cells. Furthermore, the inhibition of
autophagy suppressed RANKL mediated chemoresistance in breast cancer cells. We found
STAT3 signaling pathway was involved in RANKL-induced autophagy. Analysis of the expression
of RANK, and autophagy and STAT3 signaling associated genes in breast cancer tissues
showed that the expression of autophagy and STAT3 signaling associated genes was correlated
with the prognosis of breast cancer patients.
Conclusion
The present study suggests that the RANKL/RANK axis may potentially mediate chemoresistance
in breast cancer cells by inducing autophagy through the STAT3 signaling pathway.
Keywords
Abbreviations:
RANKL (receptor activator of nuclear factor-kappa B ligand), RANK (receptor activator of nuclear factor-kappa B), STAT3 (signal transducer and activator of transcription 3), LC3-II (Microtubule-associated protein 1 light chain 3 isoform II), ATG5 (autophagy-related 5), TNBC (triple-negative breast cancer), DMEM (Dulbecco's modified Eagle's medium), FBS (fetal bovine serum), GADPH (glyceraldehyde-3-phosphate dehydrogenase), PBS (phosphate-buffered saline), ADM (Adriamycin), 5-FU (5-fluorouracil), CQ (chloroquine), CCK8 (cell counting kit-8), OD (optical density), qRT-PCR (Quantitative real-time polymerase chain reaction), GFP (green fluorescent protein), ECL (enhanced chemiluminescence), shRNA (short hairpin RNA), TCGA (The Cancer Genome Atlas), MAP1LC3 (microtubule-associated protein 1 light chain 3), CSCs (Cancer stem cells), JAK (Janus protein tyrosine kinase), SOCS (suppressor of cytokine signaling), PTPN (protein tyrosine phosphatase non-receptor type)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 06, 2023
Accepted:
January 31,
2023
Received in revised form:
January 30,
2023
Received:
August 3,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Published by Elsevier Inc.
