Suppressed expression of Cbl‐b by <i>NF‐κB</i> mediates icotinib resistance in EGFR‐mutant non‐small‐cell lung cancer

Zhang, Tieqiong; Zheng, Chunlei; Hou, Kezuo; Wang, Jinyao; Zhang, Ye; Fan, Yibo; Zhao, Huan; Qu, Xiujuan; Liu, Yunpeng; Kang, Jian; Che, Xiaofang; Hu, Xuejun

doi:10.1002/cbin.11026

Cited by 9 publications

(2 citation statements)

References 26 publications

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“…It is well documented that NF-κB contributes to drug resistance in many different cancers [35][36][37][38]. In CML, NF-κB is activated by proteins like COBL11 [39] and TPL2 [40], and NF-κB inhibition was shown to sensitize TKI-resistant CML cells to imatinib [41][42][43][44].…”

Section: Nuclear Nf-κb Transcriptional Activity Is Increased In Tki-rmentioning

confidence: 99%

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

et al. 2021

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Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have revolutionized therapy for chronic myeloid leukemia (CML), paving the way for clinical development in other diseases. Despite success, targeting leukemic stem cells and overcoming drug resistance remain challenges for curative cancer therapy. To identify drivers of kinase-independent TKI resistance in CML, we performed genome-wide expression analyses on TKI-resistant versus sensitive CML cell lines, revealing a nuclear factor-kappa B (NF-κB) expression signature. Nucleocytoplasmic fractionation and luciferase reporter assays confirmed increased NF-κB activity in the nucleus of TKI-resistant versus sensitive CML cell lines and CD34+ patient samples. Two genes that were upregulated in TKI-resistant CML cells were proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), both members of the 19S regulatory complex in the 26S proteasome. PSMD1 and PSMD3 were also identified as survival-critical genes in a published small hairpin RNA library screen of TKI resistance. We observed markedly higher levels of PSMD1 and PSMD3 mRNA in CML patients who had progressed to the blast phase compared with the chronic phase of the disease. Knockdown of PSMD1 or PSMD3 protein correlated with reduced survival and increased apoptosis in CML cells, but not in normal cord blood CD34+ progenitors. Luciferase reporter assays and immunoblot analyses demonstrated that PSMD1 and PSMD3 promote NF-κB protein expression in CML, and that signal transducer and activator of transcription 3 (STAT3) further activates NF-κB in scenarios of TKI resistance. Our data identify NF-κB as a transcriptional driver in TKI resistance, and implicate PSMD1 and PSMD3 as plausible therapeutic targets worthy of future investigation in CML and possibly other malignancies.

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Section: Nuclear Nf-κb Transcriptional Activity Is Increased In Tki-rmentioning

confidence: 99%

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

et al. 2021

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“…For instance, casitas b-lineage lymphoma-b (Cbl-b) increased the sensitivity of gastric cancer cells to cetuximab at least partially by affecting EGFR expression [ 157 ]. Cbl-b overexpression partially reversed drug resistance to icotinib in EGFR-mutant NSCLC cells [ 158 ]. In human pancreatic cancer, low expression of Cbl conferred chemoresistance via stress-induced EGFR activation [ 159 ].…”

Section: Regulation Of Targeted Therapy Through Modulating Protein De...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

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CD73 Downregulation Decreases In Vitro and In Vivo Glioblastoma Growth

et al. 2018

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Glioblastoma is the worst and most common primary brain tumor. Here, we demonstrated the role of CD73, an enzyme responsible for adenosine (ADO) production, in glioblastoma progression. ADO increased glioma cell viability via A1 receptor sensitization. CD73 downregulation decreased glioma cell migration and invasion by reducing metalloproteinase-2 and vimentin expression and reduced cell proliferation by 40%, which was related to necrosis and sub-G1 phase blockage of cell cycle. Those effects also involved the stimulation of Akt/NF-kB pathways. Additionally, CD73 knockdown or enzyme inhibition potentiated temozolomide cytotoxic effect on glioma cells by decreasing the IC value and sensitizing cells to a non-cytotoxic drug concentration. CD73 inhibition also decreased in vivo rat glioblastoma progression. Delivery of siRNA-CD73 or APCP reduced tumor size by 45 and 40%, respectively, when compared with control. This effect was followed by a parallel 95% reduction of ADO levels in cerebrospinal fluid, indicating the role of extracellular ADO in in vivo glioma growth. Treatment did not induce systemic damage or mortality. Altogether, we conclude that CD73 is an interesting target for glioblastoma treatment and its inhibition may provide new opportunities to improve the treatment of brain tumors. Graphical Abstract ᅟ.

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Suppressed expression of Cbl‐b by NF‐κB mediates icotinib resistance in EGFR‐mutant non‐small‐cell lung cancer

Cited by 9 publications

References 26 publications

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

Protein degradation: expanding the toolbox to restrain cancer drug resistance

CD73 Downregulation Decreases In Vitro and In Vivo Glioblastoma Growth

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