Abstract
BackgroundRetinoids are potent growth inhibitory and differentiating agents in a variety of cancer cell types. We have shown that retinoids induce growth arrest in all pancreatic cancer cell lines studied, regardless of their p53 and differentiation status. However, the mechanism of growth inhibition is not known. Since TGF-β2 is markedly induced by retinoids in other cancers and mediates MUC4 expression in pancreatic cancer cells, we investigated the role of TGF-β in retinoic acid-mediated growth inhibition in pancreatic cancer cells.ResultsRetinoic acid markedly inhibited proliferation of two cell lines (Capan-2 and Hs766T) in a concentration and time-dependent manner. Retinoic acid increased TGF-β2 mRNA content and secretion of the active and latent forms of TGF-β2 (measured by ELISA and bioassay). The concentrations of active and TGF-β2 secreted in response to 0.1 – 10 μM retinoic acid were between 1–5 pM. TGF-β2 concentrations within this range also inhibited proliferation. A TGF-β neutralizing antibody blocked the growth inhibitory effects of retinoic acid in Capan-2 cells and partially inhibitory the effects in Hs766T cells.ConclusionThese findings indicate that TGF-β can cause growth inhibition of pancreatic cancer cells, in a p53-independent manner. Furthermore, it demonstrates the fundamental role of TGF-β in growth inhibition in response to retinoic acid treatment is preserved in vitro.
Highlights
Retinoids are potent growth inhibitory and differentiating agents in a variety of cancer cell types
PM falls within the active range of TGF-β2 measured by enzymelinked immunosorbent assay (ELISA). These results indicate that the amount of active TGF-β2 secreted by the pancreatic cancer cells in response to retinoic acid is capable of mediating the growth inhibitory effects of the retinoic acid
We have reported that cell lines that were previously shown to be resistant to the growth inhibitory effects of retinoic acid, were responsive when growth conditions were optimized
Summary
Retinoids are potent growth inhibitory and differentiating agents in a variety of cancer cell types. We have shown that retinoids induce growth arrest in all pancreatic cancer cell lines studied, regardless of their p53 and differentiation status. Since TGF-β2 is markedly induced by retinoids in other cancers and mediates MUC4 expression in pancreatic cancer cells, we investigated the role of TGF-β in retinoic acid-mediated growth inhibition in pancreatic cancer cells. Patients with acute promyelocytic leukemia are sensitive to retinoic acid treatment. Their response rates are in the range of 90% with retinoic acid monotherapy [5]. Retinoic acid can arrest growth in a number of different cell types [6,7]
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