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Andrographolide targets EGFR to impede epithelial–mesenchymal transition in human breast cancer cells
(2024-09-15)
Kaewpiboon, Chutima
;
Boonnak, Nawong
;
Salae, Abdul Wahab
;
Pakdeepromma, Sirichatnach
;
Yawut, Natpaphan
Despite the primary surgical treatment for breast cancer patients, malignant invasiveness and metastasis remain threatening factors for women with breast cancer. As chemotherapy yields unsatisfactory results, it prompted us to search for effective natural agents with few side-effects. Although andrographolide (ADGL), a natural diterpenoid lactone isolated from Andrographis paniculata, presents anticancer effects, the molecular mechanism remains unknown. Initially, on comparing the expression of proteins related to epithelial–mesenchymal transition (EMT) between nonmetastatic cancer MCF7 cells and highly metastatic cancer MDA-MB-231 cells, we found that MDA-MB-231 cells exhibit higher protein levels of N-cadherin and vimentin and lower protein levels of E-cadherin when compared to MCF7 cells. Moreover, MDA-MB-231 cells also exhibited higher EGFR expression and activity, higher STAT1 activity and abundant HDAC4 expression. To elucidate whether these proteins are closely associated with EMT, EGFR, STAT1 or HDAC4, the proteins were silenced in MDA-MB-231 breast cancer cells by their specific siRNAs. We found that silencing these proteins reduced EMT, indicating an important role of EGFR, STAT1 and HDAC4 in EMT progression. When we treated MDA-MB-231 cells with ADGL as a potential therapeutic drug, we found that ADGL treatment inhibited cell migration and invasion. Furthermore, it also recovered E-cadherin expression and decreased N-cadherin and vimentin protein levels. ADGL treatment reduced EGFR expression at a lower concentration (1 μg/mL); however, STAT1 activity and HDAC4 expression was reduced by a higher concentration (5 μg/mL) of ADGL. Moreover, we observed that the combined treatment with ADGL and siRNAs against these proteins highly sensitized the MDA-MB-231 cells to apoptosis compared to that with ADGL and control siRNA. Collectively, our results suggest that ADGL targets EGFR, thereby inhibiting EMT in human breast cancer cells.
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Elevated Expression of JMJD5 Protein Due to Decreased miR-3656 Levels Contributes to Cancer Stem Cell-like Phenotypes under Overexpression of Cancer Upregulated Gene 2
(2022-01-01)
Yawut, Natpaphan
;
Cho, Il Rae
;
Budluang, Phatcharaporn
;
Kaowinn, Sirichat
;
Kaewpiboon, Chutima
Overexpression of cancer upregulated gene (CUG) 2 induces cancer stem cell-like phe-notypes, such as enhanced epithelial-mesenchymal transition, sphere formation, and doxorubicin resistance. However, the precise mechanism of CUG2-induced oncogenesis remains unknown. We evaluated the effects of overexpression of CUG2 on microRNA levels using a microRNA microarray. Levels of miR-3656 were decreased when CUG2 was overexpressed; on the basis of this result, we further examined the target proteins of this microRNA. We focused on Jumonji C domain-containing protein 5 (JMJD5), as it has not been previously reported to be targeted by miR-3656. When CUG2 was overexpressed, JMJD5 expression was upregulated compared to that in control cells. A 3′ un-translated region (UTR) assay revealed that an miR-3656 mimic targeted the JMJD5 3′ UTR, but the miR-3656 mimic failed to target a mutant JMJD5 3′ UTR, indicating that miR-3656 targets the JMJD5 transcript. Administration of the miR-3656 mimic decreased the protein levels of JMD5 according to Western blotting. Additionally, the miR-3656 mimic decreased CUG2-induced cell migration, evasion, and sphere formation and sensitized the cells to doxorubicin. Suppression of JMJD5, with its small interfering RNA, impeded CUG2-induced cancer stem cell-like phenotypes. Thus, overexpression of CUG2 decreases miR-3656 levels, leading to upregulation of JMJD5, eventually contributing to cancer stem cell-like phenotypes.
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Overexpression of cancer upregulated gene 2 (Cug2) decreases spry2 through c-cbl, leading to activation of egfr and β-catenin signaling
(2020-01-01)
Yawut, Natpaphan
;
Kaewpiboon, Chutima
;
Budluang, Phatcharaporn
;
Cho, Il Rae
;
Kaowinn, Sirichat
Purpose: The mechanism by which cancer upregulated gene 2 (CUG2) overexpression induces cancer stem cell-like phenotypes is not fully understood. Because the increased activity and expression of epidermal growth factor receptor (EGFR) kinase have been reported in A549 cancer cells overexpressing CUG2 (A549-CUG2) compared with control cells (A549-Vec), the Sprouty2 (Spry2) protein has gained attention as the downstream molecule of EGFR signaling. Therefore, we aim to identify the role of Spry2 in CUG2overexpressing lung cancer cells. Materials and Methods: Spry2 expression levels were examined in A549-CUG2 and A549-Vec cells by Western blotting and qRT-PCR. Cell migration, invasion, and sphere formation were examined after Spry2 suppression and overexpression. EGFR-Stat1 and AktERK protein phosphorylation levels were detected via immunoblotting. NEK2 kinase and βcatenin reporter assay were performed for downstream of Spry2 signaling. Results: Although A549-CUG2 cells showed lower levels of the Spry2 protein than A549Vec cells, no difference in levels of Spry2 transcript was observed between both cells via qRT-PCR. Furthermore, MG132 treatment enhanced the protein levels and ubiquitination of Spry2, suggesting that Spry2 protein expression can be regulated via the ubiquitinproteasome pathway. The enforced expression of c-Cbl, known as the binding partner of Spry2, decreased the Spry2 protein levels, whereas its knockdown oppositely increased them. Epithelial–mesenchymal transition (EMT) and sphere formation were increased in A549-Vec cells during Spry2 siRNA treatment, confirming the role of Spry2 in CUG2-induced oncogenesis. Furthermore, EMT and sphere formation were determined by the Spry2 protein levels through the regulation of EGFR-Stat1 and β-catenin-NEK2-Yap1 signaling pathways. Conclusion: CUG2 reduces Spry2 protein levels, the negative signaling molecule of cell proliferation, via c-Cbl, possibly activating the EGFR and β-catenin signaling pathways and, in turn, contributing to the induction of cancer stem cell-like phenotypes.

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