Gambogenic acid induces proteasomal degradation of CIP2A and sensitizes hepatocellular carcinoma to anticancer agents

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is overexpressed in many human malignancies. It regulates phosphorylated AKT and stabilizes c‑Myc in cell proliferation and tumor formation, suggesting that CIP2A plays an essential role in the development of cancer. In the present study, we report that a natural compound, gambogenic acid (GEA), induced the degradation of CIP2A via the ubiquitin‑proteasome pathway. Interestingly, the combination of GEA and proteasome inhibitors potentiated the accumulation of ubiquitinated CIP2A and aggresome formation. In addition, GEA exhibited an inhibitory effect on cell proliferation and CIP2A‑downstream signaling molecules (c‑Myc and pAKT). Furthermore, GEA and CIP2A silencing enhanced the chemosensitivity of hepatocellular carcinoma cells to anticancer agents, suggesting that a combination of a CIP2A inhibitor and anticancer agents could be a valuable clinical therapeutic strategy. These results indicate that GEA is a CIP2A inhibitor that interferes with the ubiquitination and destabilization of CIP2A, providing a promising strategy to enhance the combinational therapy for hepatocellular carcinoma.

Preparation and preliminary pharmacokinetics study of GNA-loaded zein nanoparticles

“…Gambogenic acid (GNA, Figure ), a dry gum resin of the Garcinia genus, is a main anticancer active component derived from traditional Chinese medicine gamboge …”

“…Recent studies have showed that GNA possess strong antitumour activity to melanoma cells, gastric carcinoma cells, liver cancer cells and other cancer cells . Li et al .…”

“…Gambogenic acid (GNA, Figure 1), a dry gum resin of the Garcinia genus, is a main anticancer active component derived from traditional Chinese medicine gamboge. [1][2][3] Recent studies have showed that GNA possess strong antitumour activity to melanoma cells, [4,5] gastric carcinoma cells, [6] liver cancer cells [2] and other cancer cells. [7] Li et al [8] reported that GNA exhibited antitumour activity by inhibiting the proliferation and metastasis.…”

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

“…It has been widely proven PP2A is a tumor suppressor since the initial recognition that its inhibitor okadaic acid (OA) is a tumor promoter . However, PP2A is genetically inactivated in many types of cancer while the expression of cancerous inhibitor of PP2A (CIP2A) has been proven in many kinds of malignancy such as human hepatocellular carcinoma (HCC), colon cancer, and cervical cancer . HCC remains a major health problem and ranks the fifth most common cancer around the world.…”

“…3 However, PP2A is genetically inactivated in many types of cancer while the expression of cancerous inhibitor of PP2A (CIP2A) has been proven in many kinds of malignancy such as human hepatocellular carcinoma (HCC), colon cancer, and cervical cancer. [4][5][6] HCC remains a major health problem and ranks the fifth most common cancer around the world. Currently, the treatment of the cancer is not satisfactory, and the discovery of new therapeutic agents is in demand.…”