CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Liu Guangyi,Wang Huan,Ran Rui,Wang Yicheng,Li Yang
Background: Chemotherapy resistance is one of the main causes of clinical
chemotherapy failure. Current cancer research explores the drug resistance mechanism
and new therapeutic targets. This work aims to elucidate the mechanism of thyroid hormone
receptor interactor 13 (TRIP13) affecting doxorubicin (DOX) resistance in colorectal
cancer (CRC).
Methods: Bioinformatics analyses were employed to clarify TRIP13 expression in CRC
tissues and predict the correlation of the TRIP13 enrichment pathway with glycolysis-related
genes and stemness index mRNAsi. Quantitative real-time polymerase chain reaction
and western blot were adopted to analyze the expression of TRIP13 and glycolysis-
related genes. Cell Counting Kit-8 was utilized to determine the cell viability and
IC50 value. Western blot was employed to measure the expression of stemness-related
factors. Cell function assays were performed to detect cells' sphere-forming ability and
glycolysis level. Animal models were constructed to determine the effects of TRIP13 expression
on CRC tumor growth.
Results: TRIP13 was significantly overexpressed in CRC, concentrated in the glycolysis
signaling pathway, and positively correlated with stemness index mRNAsi. High expression
of TRIP13 facilitated DOX resistance in CRC. Further mechanistic studies revealed
that overexpression of TRIP13 could promote cell stemness through glycolysis, which
was also confirmed in animal experiments.
Conclusion: TRIP13 was highly expressed in CRC, which enhanced the DOX resistance
of CRC cells by activating glycolysis to promote cell stemness. These findings offer
new insights into the pathogenesis of DOX resistance in CRC and suggest that
TRIP13 may be a new target for reversing DOX resistance in CRC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
细胞生物学
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DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-15
·
IF 3.8
Ding Yangyang,Huang Keke,Sun Cheng,Liu Zelin,Zhu Jinli,Jiao Xunyi,Liao Ya,Feng Xiangjiang,Guo Jingjing,Zhu Chunhua,Zhai Zhimin,Xiong Shudao
Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/β-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
·
癌症治疗
·
基因组学
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DOI
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2026
·
IF 4.3
Xingzi Guo,Jie Tang,He Li,Saiping Mao,Yan-Xiang Tang,Zhen-Zi Tang,Lianghui Gong
Ovarian cancer (OC) is associated with high mortality and frequent resistance to poly (ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, particularly in patients with breast cancer gene (BRCA)-proficient tumors. To explore the potential mechanisms underlying Olaparib resistance, Olaparib-resistant OC cell lines were established through stepwise drug induction. Candidate resistance-related genes were screened using bioinformatic analyses and subsequently validated in clinical specimens. Their biological functions and underlying mechanisms were further investigated through gene silencing, co-immunoprecipitation, immunofluorescence, comet assays, and an OVCAR3 xenograft model. Bioinformatic analyses indicated that TRIP13 and KNTC1 were highly expressed in Olaparib-resistant cells and were associated with poor prognosis. Their elevated expression was further confirmed by RT-qPCR, western blotting, and immunohistochemistry. Functional studies showed that silencing either TRIP13 or KNTC1 inhibited cell proliferation and induced apoptosis in Olaparib-resistant OC cells. Mechanistically, co-immunoprecipitation and immunofluorescence analyses confirmed a cytoplasmic interaction between TRIP13 and KNTC1. TRIP13 knockdown impaired non-homologous end joining (NHEJ)-mediated DNA repair, as evidenced by decreased expression of NHEJ-related proteins, increased γH2AX accumulation, and enhanced comet tail formation. Conversely, TRIP13 overexpression promoted NHEJ repair and reduced Olaparib-induced DNA damage, whereas these effects were partially reversed by the NHEJ inhibitor SCR130. In vivo , TRIP13 overexpression promoted tumor growth and reduced sensitivity to Olaparib, while KNTC1 knockdown reversed these effects. Collectively, these findings suggest that TRIP13 and KNTC1 cooperatively promote NHEJ-mediated DNA repair, thereby contributing to Olaparib resistance in BRCA-proficient OC. Targeting the TRIP13/KNTC1 axis may therefore enhance the therapeutic efficacy of Olaparib and provide a promising strategy for overcoming PARP inhibitor resistance.
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DOI
PubMed
高影响因子
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