Proprotein convertases blockage up-regulates specifically metallothioneins coding genes in human colon cancer stem cells

Gerovska, Daniela; García-Gallastegi, Patricia; Descarpentrie, Jean; Crende, Olatz; Casado-Andrés, María; Martín, Ander; Eguia, Jokin; Khatib, Abdel‐Majid; Araúzo‐Bravo, Marcos J.; Badiola, Iker

doi:10.1016/j.bbamcr.2020.118912

Cited by 3 publications

(3 citation statements)

References 65 publications

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“…The study also identified dysregulated expression of several calcium regulators in cancer cells with these mutations lacking Furin activity. Taken together with the previous studies [ 31 , 32 , 33 , 34 ], the present findings suggest that the ability of reagents that interfere with PCs, particularly Furin, could potentially have therapeutic effects by regulating calcium regulators in colon cancer with KRAS or BRAF mutation.…”

Section: Discussionsupporting

confidence: 83%

“…The most promising protein-based specific inhibitors of PCs are the individual PC-pro-segment-based inhibitors, the serpin variant α1-PDX and the serpin Spn4A [ 26 , 27 , 28 , 29 , 30 ]. Previously, the inhibition of the convertases in CSCs was associated with upregulated expression of various metallothioneins known as tumor suppressor genes, of which the loss in colon cancer patients was associated with bad prognosis [ 31 ]. On the other hand, Furin was reported to interfere with calcium mobilization [ 29 , 32 ], and PCs repression reduced the malignant phenotype of cancer cells and resistance to apoptotic agents [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

Descarpentrie

Araúzo-Bravo

et al. 2022

Cancers

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Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca2+-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers’ expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

Descarpentrie

Araúzo-Bravo

et al. 2022

Cancers

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“…In addition to tumor immune evasion, the recently proposed “cancer stem cell” theory posits that cancer stem cells (CSCs) also ultimately result in resistance to treatment and cancer recurrence [ 13 , 14 ]. CSCs are resistant to current therapies compared with cancer cells because most of these cells are maintained in a resting state, whereas existing therapies target proliferating tumor cells [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway

Wang

Choi

et al. 2021

Antioxidants

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Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the current study, we first confirmed the anti-inflammatory effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), a novel DHA dihydroxy derivative synthesized in our previous work. We found that diHEP-DPA significantly reduced lipopolysaccharide (LPS)-induced inflammatory cytokines secretion of THP1 macrophages, IL-6, and TNF-α. As expected, diHEP-DPA also modulated TAM polarization, as evidenced by decreased gene and protein expression of the TAM markers, CD206, CD163, VEGF, and TGF-β1. During the polarization process, diHEP-DPA treatment decreased the concentration of TGF-β1, IL-1β, IL-6, and TNF-α in culture supernatants via inhibiting the NF-κB pathway. Moreover, diHEP-DPA blocked immunosuppression by reducing the expression of SIRPα in TAMs and CD47 in colorectal cancer cells. Knowing that an inflammatory TME largely serves to support epithelial-mesenchymal transition (EMT) and cancer stemness, we tested whether diHEP-DPA acted through polarization of TAMs to regulate these processes. The intraperitoneally injected diHEP-DPA inhibited tumor growth when administered alone or in combination with 5-fluorouracil (5-FU) chemotherapy in vivo. We further found that diHEP-DPA effectively reversed TAM-conditioned medium (TCCM)-induced EMT and enhanced colorectal cancer stemness, as evidenced by its inhibition of colorectal cancer cell migration, invasion and expression of EMT markers, as well as cancer cell tumorspheres formation, without damaging colorectal cancer cells. DiHEP-DPA reduced the population of aldehyde dehydrogenase (ALDH)-positive cells and expression of colorectal stemness marker proteins (CD133, CD44, and Sox2) by modulating TAM polarization. Additionally, diHEP-DPA directly inhibited cancer stemness by inducing the production of reactive oxygen species (ROS), which, in turn, reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). These data collectively suggest that diHEP-DPA has the potential for development as an anticancer agent against colorectal cancer.

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Inhibition of proprotein convertases activity results in repressed stemness and invasiveness of cancer stem cells in gastric cancer

Zaafour,

Seeneevassen,

Nguyen

et al. 2024

Gastric Cancer

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Proprotein convertases blockage up-regulates specifically metallothioneins coding genes in human colon cancer stem cells

Cited by 3 publications

References 65 publications

Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway

Inhibition of proprotein convertases activity results in repressed stemness and invasiveness of cancer stem cells in gastric cancer

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