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TGF‐β acts as a dual regulator of COX‐2/PGE 2 tumor promotion depending of its cross‐interaction with H‐ Ras and Wnt/β‐catenin pathways in colorectal cancer cells
Author(s) -
Araújo Wallace M.,
Tanaka Marcelo N.,
Lima Pedro H. S.,
Moraes Cassio F.,
Leve Fernanda,
Bastos Lilian G.,
Rocha Murilo R.,
Robbs Bruno K.,
Viola João P. B.,
MorgadoDiaz Jose A.
Publication year - 2021
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.11519
Subject(s) - wnt signaling pathway , cancer research , oncogene , transforming growth factor , colorectal cancer , tumor promotion , catenin , cancer , biology , chemistry , cell cycle , medicine , signal transduction , endocrinology , microbiology and biotechnology , carcinogenesis
Transforming growth factor‐β (TGF‐β) plays a dual role acting as tumor promoter or suppressor. Along with cyclooxygenase‐2 (COX‐2) and oncogenic Ras , this multifunctional cytokine is deregulated in colorectal cancer. Despite their individual abilities to promote tumor growth and invasion, the mechanisms of cross regulation between these pathways is still unclear. Here, we investigate the effects of TGF‐β, Ras oncogene and COX‐2 in the colorectal cancer context. We used colon adenocarcinoma cell line HT‐29 and Ras ‐transformed IEC‐6 cells, both treated with prostaglandin E 2 (PGE 2 ), TGF‐β or a combined treatment with these agents. We demonstrated that PGE 2 alters the subcellular localization of E‐cadherin and β‐catenin and enhanced the tumorigenic potential in HT‐29 cells. This effect was inhibited by TGF‐β, indicating a tumor suppressor role. Conversely, in Ras ‐transformed IEC‐6 cells, TGF‐β induced COX‐2 expression and increased invasiveness, acting as a tumor promoter. In IEC‐6 Ras‐transformed cells, TGF‐β increased nuclear β‐catenin and Wnt/β‐catenin activation, opposite to what was seen in the PGE 2 and TGF‐β joint treatment in HT‐29 cells. Together, our findings show that TGF‐β increases COX‐2 levels and induces invasiveness cooperating with Ras in a Wnt/β‐catenin activation‐dependent manner. This shows TGF‐β dual regulation over COX‐2/PGE 2 tumor promotion depending on the H‐ Ras and Wnt/β‐catenin pathways activation status in intestinal cancer cells.