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A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid.

ABSTRACT: Cancer stem cells (CSCs) have been identified in a multiple of cancer types and resistant to traditional cancer therapies such as chemotherapeutic agents and radiotherapy, which may destroy bulk tumor cells but not all CSCs, contributing to reformation tumor masses and subsequent relapse. Moreover, it is very difficult to effectively identify and eliminate CSCs because they share some common phenotypic and functional characteristics of normal stem cells. Therefore, finding better therapeutic strategies to selectively target CSCs might be helpful to reduce subsequent malignancies. In the present study, we found that caffeic acid effectively suppresses self-renewal capacity, stem-like characteristics, and migratory capacity of CD44⁺ and CD133⁺ colorectal CSCs in vitro and in vivo. In addition, we also revealed that PI3K/Akt signaling may be linked to multiple colorectal CSC-associated characteristics, such as radio-resistance, stem-like property, and tumorigenic potential. To the best of our knowledge, this is the first study demonstrating that caffeic acid effectively targets colorectal CSC populations by inhibiting the growth and/or self-renewal capacity of colorectal CSCs through PI3K/Akt signaling in vitro and in vivo.

SUBMITTER: Park SR

PROVIDER: S-EPMC7785810 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid.

Park Se-Ra SR Kim Soo-Rim SR Hong In-Sun IS Lee Hwa-Yong HY

Frontiers in cell and developmental biology 20201223

Cancer stem cells (CSCs) have been identified in a multiple of cancer types and resistant to traditional cancer therapies such as chemotherapeutic agents and radiotherapy, which may destroy bulk tumor cells but not all CSCs, contributing to reformation tumor masses and subsequent relapse. Moreover, it is very difficult to effectively identify and eliminate CSCs because they share some common phenotypic and functional characteristics of normal stem cells. Therefore, finding better therapeutic str ...[more]

PMID: 33425893

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Project description:Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE treatment decreased the interaction of AKT with XIAP. To establish the involvement of AKT in the apoptosis-inducing effects of CAPE, cells were transfected with AKT. Our results revealed that AKT overexpression attenuated the decrease in XIAP and significantly blocked CAPE-mediated apoptosis. Similarly, overexpression of XIAP further decreased CAPE-induced apoptosis. Taken together, our results suggest that CAPE suppresses phosphoinositide 3-kinase/AKT/XIAP pathway leading to apoptosis in melanoma tumor cells in vitro and in vivo.

Project description:BackgroundConsiderable evidence suggests that tumor initiation, malignancy, metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). Fas binding factor 1 (FBF1) is a multifunctional protein that plays essential roles in the regulation of development and cell fate decisions. However, the function in maintaining stem cell-like properties of breast cancer remains elusive.MethodsTissue microarray was used to evaluate FBF1 expression. Cancer stemness assays were performed in FBF1 silencing and overexpressing cells in vitro and in a xenograft model in vivo. RNA sequencing, immunofluorescence and immunoprecipitation assays were performed to explore the underlying mechanism. Clinical expression and significance of FBF1 and stemness-associated factors were explored by analyzing datasets.ResultsWe report that FBF1 was highly expressed in breast cancer and significantly correlated with clinical progression. Silencing FBF1 in MDA-MB-231 cells restrained CSCs properties, including side population, sphere formation and migration, whereas ectopic FBF1 expression increased the side population proportion, enhanced the sphere formation ability, and promoted the expression of core stemness genes, such as SOX2, OCT4, KLF4 and NANOG, as well as facilitated metastasis of T47D breast cancer cells. Furthermore, mice bearing FBF1-overexpressed T47D xenografts had higher tumorigenic frequency and stronger metastasis potential. In addition, exploration of the underlying mechanism indicated that FBF1 binds PI3K which then activates PI3K-AKT phosphorylation cascades. Then the activated p-AKT interacts with stemness marker SOX2, elevates SOX2 and OCT4 activity, and finally forms PI3K/AKT/SOX2 axis, which mediates stem cell-like identities. Moreover, PI3K inhibitors abolished FBF1-mediated signaling pathway and diminished breast cancer stemness in vitro and in vivo. In 24 human breast cancer samples, we found a good positive correlation between the expression of FBF1 and p-AKT, as well as between FBF1 and SOX2 as determined by IHC. Clinical data showed that FBF1 expression was positively correlated with the expression of POU5F1 (OCT4), AKT1 and was negatively correlated with PTEN, which is a negative regulator of PI3K/AKT signaling.ConclusionCollectively, we identified a potential CSCs regulator and suggested a novel mechanism by which FBF1 governs cancer cell stemness. This study thus introduces an effective target for the diagnosis and treatment of breast cancer.

Dataset Information

A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid.

Publications

A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid.

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