Abstract
BackgroundWe recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A) functions as a tumor suppressor in human pancreatic tumor cells. Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Preclinical studies using ATRA for treating human pancreatic cancer suggest this compound might be useful for treatment of pancreatic cancer patients. However, the molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRA-mediated growth inhibition of human pancreatic tumor cells.ResultsWe performed microarray studies using HEK 293T cells and discovered that Chmp1A positively regulated Cellular retinol-binding protein 1 (CRBP-1). CRBP-1 is a key regulator of All-trans retinoic acid (ATRA) through ATRA metabolism and nuclear localization. Since our microarray data indicates a potential involvement of Chmp1A in ATRA signaling, we tested this hypothesis by treating pancreatic tumor cells with ATRA in vitro. In the ATRA-responsive cell lines, ATRA significantly increased the protein expression of Chmp1A, CRBP-1, P53 and phospho-P53 at serine 15 and 37 position. We found that knockdown of Chmp1A via shRNA abolished the ATRA-mediated growth inhibition of PanC-1 cells. Also, Chmp1A silencing diminished the increase of Chmp1A, P53 and phospho-P53 protein expression induced by ATRA. In the ATRA non-responsive cells, ATRA did not have any effect on the protein level of Chmp1A and P53. Chmp1A over-expression, however, induced growth inhibition of ATRA non-responsive cells, which was accompanied by an increase of Chmp1A, P53 and phospho-P53. Interestingly, in ATRA responsive cells Chmp1A is localized to the nucleus, which became robust upon ATRA treatment. In the ATRA-non-responsive cells, Chmp1A was mainly translocated to the plasma membrane upon ATRA treatment.ConclusionCollectively our data provides evidence that Chmp1A mediates the growth inhibitory activity of ATRA in human pancreatic cancer cells via regulation of CRBP-1. Our results also suggest that nuclear localization of Chmp1A is important in mediating ATRA signaling.
Highlights
We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A) functions as a tumor suppressor in human pancreatic tumor cells
Chmp1A mRNA expression was examined as positive control for Reverse transcriptase PCR (RT-PCR) which was increased 1.9 fold by Chmp1A over-expression compared to control (Figure 1A)
Since Cellular retinol-binding protein 1 (CRBP-1) is involved in retinoid metabolism and function we developed a hypothesis that Chmp1A might be involved in All-trans retinoic acid (ATRA) signaling
Summary
We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A) functions as a tumor suppressor in human pancreatic tumor cells. The molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRAmediated growth inhibition of human pancreatic tumor cells. Nuclear receptors and cellular binding proteins are involved in mediating the biological effects of retinoids [1,2,3,4]. The active form of retinoids (ATRA or 9-cis-RA) interacts with their nuclear receptors, retinoic acid receptors (RAR α, β, and γ), and retinoic × receptors (RXR α, β, and γ). All-trans retinoic acid (ATRA) is one of the most physiologically active members of the retinoid family. By binding to its receptor RAR, ATRA exercises a broad spectrum of biological effects such as proliferation and differentiation [5]. Because of anti-proliferative effects of ATRA, it has been used as a therapeutic and/or preventive agent in certain cancers such as promyelocytic leukemia [6]
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