Impact of FAK Expression on the Cytotoxic Effects of CIK Therapy in Triple-Negative Breast Cancer

Pan, Mei-Ren; Wu, Cheng-Che; Kan, Jung‐Yu; Li, Qiao-Lin; Chang, Shu-Jyuan; Wu, Chun‐Chieh; Li, Chung-Liang; Ouyang, Fusheng; Hou, Ming‐Feng; Yip, Hon‐Kan; Luo, Chi-Wen

doi:10.3390/cancers12010094

Cited by 25 publications

(23 citation statements)

References 60 publications

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“…Of note, FAK over-expression has been tightly correlated with the malignant grade [66] as well as the poor clinical outcome in TNBC patients [22]. Moreover, FAK activation was involved in the peculiar features of TNBC [65], whereas the inhibition of FAK signaling prevented the metastatic potential of TNBC cells [22,23] and enhanced the sensitization to anti-cancer treatments [67]. However, the precise mechanism by which FAK acts in TNBC are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Rigiracciolo

Nohata

Lappano

et al. 2020

Cells

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Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.

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Section: Discussionmentioning

confidence: 99%

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Rigiracciolo

Nohata

Lappano

et al. 2020

Cells

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“…Recently, it was shown that, while not affecting primary tumor development and growth, FAK deletion significantly suppressed breast cancer metastasis in vivo [ 40 ]. Another study demonstrated that knockdown of FAK expression in TNBC cells or the treatment of TNBC cells with a FAK inhibitor followed by co-culture with cytokine-induced killer (CIK) cells increased the death of TNBC cells, suggesting that FAK plays an important role in sensitizing tumor cells to CIK cells [ 41 ]. Interestingly, our results supported the most recent study, which demonstrated that inhibition of FAK enhanced 5-FU chemosensitivity to gastric carcinoma [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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“…It experiment process is displayed in Fig.1a. After excluding the drugs that had been reported to be related to PD-L1, such as the inhibitors of MEK [27][28][29] , FAK [30][31][32][33][34] and ALK [35][36][37] , we found that amlodipine, a dihydropyridine calcium channel blocker 38 , abundantly decreased the expression of PD-L1 in cancer cells ( Supplementary Fig. 1a).…”

Section: Introductionmentioning

confidence: 99%

Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity

Yao

Wang

et al. 2020

Preprint

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SummaryCancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpains-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1 dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.

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Impact of FAK Expression on the Cytotoxic Effects of CIK Therapy in Triple-Negative Breast Cancer

Cited by 25 publications

References 60 publications

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity

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