Panoply™ Human GDF15 Over-expressing Stable Cell Line

Hypoxia plays a pivotal role in regulating epithelial-mesenchymal transition (EMT) and promoting metastasis in colorectal cancer, yet the underlying mechanisms remain incompletely understood. Here, researchers found that hypoxic exposure induces endoplasmic reticulum stress and activates the unfolded protein response (UPR) pathway, thereby driving GDF15 expression in colorectal cancer cells. Mechanistically, activation of the PERK-eIF2α signaling pathway leads to the upregulation of CHOP, which promotes GDF15 transcription by directly binding to its promoter. Further studies demonstrated that hypoxia-induced GDF15 is essential for EMT and invasion in colorectal cancer cells; forced expression of GDF15 promotes mitochondrial fatty acid oxidation within these cells. Moreover, blocking GDF15 reduces xenograft tumor volume and inhibits metastasis. GDF15 is highly expressed in tumor tissues from colorectal cancer patients, and its mRNA levels positively correlate with those of CHOP and HIF1α. These findings reveal a novel molecular mechanism by which hypoxia promotes colorectal cancer metastasis and suggest that PERK-regulated GDF15 represents a promising therapeutic target for clinical treatment and drug development.

To investigate the physiological function of GDF15, which is upregulated under hypoxic conditions, researchers examined its role in tumor cell metastasis-a process significantly promoted by hypoxia. In GDF15-overexpressing HT29 cells, the protein expression levels of genes associated with epithelial-mesenchymal transition (EMT) were significantly altered: N-cadherin and Vimentin expression increased, whereas E-cadherin expression decreased (Figure 1a). Furthermore, compared with the control group, GDF15-overexpressing HT29 cells exhibited enhanced invasive and migratory capabilities (Figure 1b and c). Consistent with the effects observed with ectopic expression, the loss of endogenous GDF15 inhibited EMT (Figure 1d)) and suppressed cell migration and invasion (Figures 1e and f). Thus, these results indicate that hypoxia-induced GDF15 plays a critical role in regulating metastasis in colorectal cancer (CRC) cells.

Figure 1. GDF15 promotes EMT and invasion of CRC cells. (Zheng H, et al., 2020)