Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain

Guo, Tao; Gu, Chao; Li, Bin; Xu, Congjian

doi:10.18632/aging.203386

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…Similarly, the concomitant use of inhibitors to abolish drug resistance has been shown to be more effective in clinical trials [ 194 , 260 ]. Another promising strategy is combination therapy with TKIs and signaling pathway inhibitors [ 194 , 237 , 261 , 262 ], as well as simultaneous inhibition of FGFRs and induction of apoptosis [ 263 , 264 , 265 ]. Ligand traps and mAbs targeting FGFR/FGF are relatively new approaches and are still relatively few in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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“…Increased BCL2L1 is related to the drug resistance of ovarian cancer to a variety of anti-cancer drugs. The double inhibition of FGFR4 and BCL2L1 has shown strong effects and tolerable toxicity ( 32 ). Thus, BCL2L1 plays an important role in the occurrence and development of tumors.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of the miR-7/BCL2L1/P53 signaling axis regulating the progression of hepatocellular carcinoma

Zhang¹,

Wang²,

Zhu³

et al. 2023

Ann Transl Med

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Background: To investigate the roles of miR-7 and its potential mechanisms in hepatocellular carcinoma (HCC).Methods: The functions of miR-7 were identified and measured by 5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide], colony formation, transwell, and flow cytometry assays. A luciferase assay was applied to verify the direct binding of miR-7 on BCL2L1 3'untranslated region (3'UTR).An in vitro experiment was then used to investigate the biological effects of miR-7 and BCL2L1. A coimmunoprecipitation (COIP) assay was used to detect the protein interaction between BCL2L1 and P53.Results: We found that miR-7 overexpression suppressed cell proliferation, migration, and invasion in HCC. BCL2L1 was also demonstrated as a direct target gene of miR-7. This study showed that BCL2L1 could partially rescue the inhibitory effect of miR-7 on the proliferation, migration, and invasion of HCC cells. Our research showed that miR-7 could inhibit the epithelial-mesenchymal transition (EMT) pathway by regulating BCL2L1. We also further confirmed that miR-7 inhibits the proliferation, migration, and invasion of Hep3B and Huh7 cells by targeting BCL2L1. Furthermore, we observed that the BCL2L1 protein interacts with the P53 protein and BCL2L1 affects the development of liver cancer through P53. We also found that BCL2L1 could promote the invasion and migration of liver cancer cells through P53 inhibition.BCL2L1 also inhibited the expression of Caspase 3/7 in hepatoma cells by inhibiting the expression of P53.Conclusions: Our study demonstrated that miR-7/BCL2L1/P53 may serve as a regulatory molecular axis for HCC treatment. Our results suggest that miR-7/BCL2L1/P53 may have predictive value and represent a new treatment strategy for liver cancer.

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“…Furthermore, based on the molecular docking results, tumulosic acid showed good binding activity to key targets, indicating that acid is likely to be the key active ingredient of Poria cocos against OC. BCL2L1 is a critical anti-apoptotic gene encoding the anti-apoptotic protein BCL-xL, an important transmembrane molecule of mitochondria that is closely associated with OC progression ( Kurita et al, 2012 ; Guo et al, 2021 ). Interestingly, the differential expression of BCL2L1 in normal and OC tissues and the survival analysis results likewise provide strong arguments for this contention ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Pharmacological Mechanism of Poria cocos-Based Formulas Combined With Chemotherapy for Ovarian Cancer: A Integrated Systems Pharmacology Study

et al. 2022

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Previous studies have shown that Poria cocos-based formulas combined with chemotherapy can improve the quality of life of ovarian cancer patients. However, the results are still controversial. We systematically searched the literature from eight databases to evaluate the efficacy and safety of Poria cocos-based formulas in combination with paclitaxel-carboplatin in treating ovarian cancer (OC). Subsequently, network pharmacology, molecular docking and cell experiments were performed to further verify the underlying molecular mechanism. Thirteen randomized controlled trials, including 922 patients with OC, were enrolled in the study. The results indicated that Poria cocos-based compounds combined with paclitaxel-carboplatin significantly improved patients’ tumor response rate, traditional Chinese medicine syndrome score, Karnofsky Performance Scale, physical and social function, and reduced side effects of chemotherapy compared to the paclitaxel-carboplatin alone. According to the network pharmacological analysis, tumulosic acid were the most bioactive compounds of Poria cocos. BCL2L1 is highly expressed in OC and is associated with a worse prognosis which could become potential drug target. Functional enrichment analysis suggested that the anti-OC effect of Poria cocos may be related to PI3K-Akt signaling pathway. The molecular docking results indicated that tumulosic acid might inhibit OC by regulating BCL2L1. Vitro experiment confirmed tumulosic acid that induced cell apoptosis by modulating PI3K/AKT signaling and BCL2L1. Our study may provide a clinical basis and theoretical rationale for combining Poria cocos-based formulas with chemotherapy for OC. In addition, the integrated pharmacological strategy proposed in our study provides an excellent example for exploring the mechanism of complex formulas.

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Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain

Cited by 15 publications

References 24 publications

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Molecular mechanism of the miR-7/BCL2L1/P53 signaling axis regulating the progression of hepatocellular carcinoma

Efficacy and Pharmacological Mechanism of Poria cocos-Based Formulas Combined With Chemotherapy for Ovarian Cancer: A Integrated Systems Pharmacology Study

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