Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer

Oncogene
Miran RadaDong-Joo Cheon

Abstract

Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cance...Continue Reading

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Citations

Sep 16, 2019·Journal of Translational Medicine·Shuaishuai XuLiang Liu
Feb 7, 2020·Journal of Gynecologic Oncology·Yongfang YueXing Xie
Nov 27, 2019·Cancers·Mudra BinjuYu Yu
Jul 25, 2019·Frontiers in Cell and Developmental Biology·Sameera NallanthighalDong-Joo Cheon
Sep 29, 2020·International Journal of General Medicine·Ali KhodadadianMajid Nazari
Nov 6, 2020·Journal of Investigative Surgery : the Official Journal of the Academy of Surgical Research·Hongbin TuLixin Wang
Jul 25, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tsz-Lun YeungSamuel C Mok
Mar 7, 2021·Cancers·Sameera NallanthighalDong-Joo Cheon
May 11, 2021·International Journal of Radiation Biology·Miaomiao ZhuXiaoyan Ying
May 18, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ziqiang LiuHaiyan Huang

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Datasets Mentioned

BETA
GSE112985

Methods Mentioned

BETA
xenograft
FACS
RNA-seq
PCR
RNAseq

Software Mentioned

FlowJo
STAR
ImageJ
GraphPad
KM plotter
GraphPad Prism
RESM
Cytoscape

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