<p>Inhibition of ERKs/Akt-Mediated c-Fos Expression Is Required for Piperlongumine-Induced Cyclin D1 Downregulation and Tumor Suppression in Colorectal Cancer Cells</p>

Abstract

Background: Deregulation of Cyclin D1 and cell cycle progression plays a critical role in tumorigenesis. The natural compound piperlongumine (PL) exhibits potential anticancer effects in various cancer models, but the underlying mechanism needs further elucidation. Methods: The inhibitory effect of PL on colorectal cancer (CRC) cells was determined by anchorage-dependent and-independent assays. The protein level of Cyclin D1 was examined by immunoblot (IB) and immunohistochemical staining (IHC). The mRNA level was determined by qRT-PCR. Phosphorylation of histone H3 was analyzed by immunofluorescence (IF). The cell cycle was examined by flow cytometry. The in vivo antitumor effect was validated by the xenograft mouse model. Results: Cyclin D1 was overexpressed in CRC tissues and cells, and was required for maintaining cell growth, colony formation, and in vivo tumorigenesis. PL decreased the protein level of c-Fos, which eventually reduced the transcriptional activity of AP-1 and the mRNA level of Cyclin D1. Mechanism study showed that PL impaired EGF-induced activation of ERK1/2 and Akt signalings, which resulted in a reduction of c-Fos transcription. Furthermore, PL reduced the half-life of c-Fos and caused the ubiquitination-dependent degradation of c-Fos. Finally, the in vivo antitumor effect of PL on CRC cells was examined using a xenograft mouse model. Conclusion: Our data indicate that PL is a promising antitumor agent that deserves further study for CRC treatment.

Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells

“…1 H, I). On the basis of these findings and in line with previous studies showing that PI3K/AKT and ERK1/2 transduction pathways mediate the expression of insulin target genes, such as c‐Fos and Cyclin D1 [ 27 , 44 – 46 ], we found that insulin induces c-Fos expression in BCAHC-1 cells at both mRNA (data not shown) and protein levels (Fig. 2 A–C).…”

Piperlongumine Alleviates Mouse Colitis and Colitis-Associated Colorectal Cancer

“…Similarly, a recent report has shown that PL could suppress tumor cell growth and proliferation in DMH/ DSS-induced experimental colon cancer by targeting Ras/PI3K/ Akt/mTOR signaling axis (Kumar and Agnihotri, 2019). PLinduced Cyclin D1 downregulation and tumor suppression in colorectal cancer cells by suppression of ERKs/Akt-mediated c-Fos expression (Gao et al, 2020). PL could also induce apoptosis by activation of JNK in colorectal cancer HCT116 cells independent of Bax, p21 and p53 status (Li et al, 2015;DA Silva Machado et al, 2018).…”

Piperlongumine‑loaded nanoparticles inhibit the growth, migration and invasion and epithelial‑to‑mesenchymal transition of triple‑negative breast cancer cells

“…At this time, the mechanism through which exposure to PL downregulates Smad3 expression and upregulates NDRG1 expression remains to be elucidated. However, PL has been reported to inhibit extracellular signal-regulated kinase 1/2 activation in colorectal cancer cells (42). A similar effect in MDA-MB-231 cells may account for the reduced Smad3 expression, since the inhibition of extracellular signal-regulated kinase signaling suppresses Smad3 expression in epithelial cells (43).…”