All‐<i>trans</i> retinoic acid reverses epithelial‐mesenchymal transition in paclitaxel‐resistant cells by inhibiting nuclear factor kappa B and upregulating gap junctions

Shi, Guiling; Zheng, Xiaoli; Wu, Xiaojing; Wang, Siqi; Wang, Yijia; Xing, Fei

doi:10.1111/cas.13855

Cited by 36 publications

(26 citation statements)

References 40 publications

(99 reference statements)

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“…For example, for over 10 years, ATRA was used in combination with paclitaxel to overcome the paclitaxel-resistance after long-term chemotherapy that establishes a phenotype with higher metastatic ability. Only recently it was showed that ATRA reverse the epithelial-mesenchymal transition associated with paclitaxel resistance inhibiting NFkB, and up-regulating the gap junctions [268].…”

Section: Tumor Progression: Cscs and Invasionmentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

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Section: Tumor Progression: Cscs and Invasionmentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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“…The PI3K-Akt pathway plays a key role in the regulation of apoptosis by NF-κB (36). NF-κB activation results in resistance to many chemotherapeutic drugs, whereas its suppression is known to provide effective therapeutic benefits in chemotherapy treatments (20,21). We found that resveratrol and cetuximab both inhibit NF-κB in these cells, and cells treated with the combination of these two agents have the lowest NF-κB level in their nuclei.…”

Section: Discussionmentioning

confidence: 80%

“…Western blotting was carried out as previously described (21). Briefly, protein samples were suspended in an SDS loading buffer.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

“…Immunofluorescence staining was used to analyze Cx43 and Akt. The procedure was carried out as described previously (21). In brief, cells were washed twice with PBS, and fixed in 10% formalin at room temperature for 20 min, treated with 0.5% Triton X-100 for 5 min at 4 • C followed by overnight blocking in 5% normal goat serum at 4 • C. Following several PBS washes, slides were incubated with a mouse anti-Cx43 antibody or rabbit anti-Akt antibody for 1 h at 37 • C. After washing with PBS, the slides were incubated with FITC-conjugated goat anti-mouse antibody and TRITC-conjugated goat anti-rabbit antibody and DAPI for 1 h at 37 • C, followed by several washes in PBS.…”

Section: Immunocytochemistry Analysismentioning

confidence: 99%

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Resveratrol Sensitizes Colorectal Cancer Cells to Cetuximab by Connexin 43 Upregulation-Induced Akt Inhibition

Wang

Wang²,

Wu³

et al. 2020

Front. Oncol.

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Cetuximab is a monoclonal antibody that acts as an anti-epidermal growth factor receptor (EGFR) agent. Cetuximab inhibits the phosphorylation and activation of EGFR and blocks downstream signal pathways of EGF/EGFR, including Ras-Raf-MAPK and PI3K-Akt pathways. Akt activation is an important factor in cetuximab resistance. It has been reported that resveratrol and connexin 43 regulate Akt in different ways based on tissue type. Since connexin 43 interacts with Akt, and resveratrol is known to upregulate connexin 43, we investigated whether resveratrol can sensitize colorectal cancer cells to cetuximab via connexin 43 upregulation. Our work confirmed that resveratrol increases the inhibition of growth by cetuximab in vitro and in vivo, upregulates connexin 43 expression and phosphorylation, increases gap junction function, and inhibits the activation of Akt and NFκB in parental or cetuximab-treated parental HCT116 and CT26 cells. Resveratrol did not exhibit these effects on connexin 43-shRNA transfected cells, so connexin 43 upregulation may contribute to Akt inhibition in these cells. Given these data, resveratrol may sensitize colorectal cancer cells to cetuximab via upregulating connexin 43 to inhibit the Akt pathway.

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“…In CRC cell lines treatment with ATRA led to decreased proliferation, sphere formation and aldehyde dehydrogenase (ALDH) + CSC-population size by inducing neuroendocrine differentiation [ 29 ]. Moreover, Shi and colleagues found evidence that ATRA reverses EMT in chemotherapy resistant CRC cell lines [ 31 ]. Furthermore, a study with NMYC -amplified neuroblastoma cells could show that a combined treatment of ATRA and a peptide derived from tenascin-C induced differentiation and led to a decrease of NMYC protein [ 27 ], highlighting the involvement of ATRA in NMYC signaling.…”

Section: Introductionmentioning

confidence: 99%

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

Esch

Windmöller

Hanewinkel

et al. 2020

Cancers

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Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.

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All‐trans retinoic acid reverses epithelial‐mesenchymal transition in paclitaxel‐resistant cells by inhibiting nuclear factor kappa B and upregulating gap junctions

Cited by 36 publications

References 40 publications

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Resveratrol Sensitizes Colorectal Cancer Cells to Cetuximab by Connexin 43 Upregulation-Induced Akt Inhibition

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

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