Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κBSTAT1STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells

Abstract EN

There are increasing evidences of proinflammatory cytokine involvement in cancer development.

Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like.

Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner.

STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation.

STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT).

IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity.

Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation.

Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation.

Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB interactions.

Oct-4 expression was also downregulated by withaferin A inhibition.

The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments.

Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells.

Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.