Mitogen‑activated protein kinase inhibition enhances the antitumor effects of sporamin in human pancreatic cancer cells

Abstract

Abstract. Sporamin, a sweet potato tuber storage protein, is a Kunitz-type trypsin inhibitor (TI) that has exhibited antitumor activity through poorly defined mechanisms in a number of types of tumor cells. The present study aimed to analyze the combined effects of sporamin and three mitogen-activated protein kinase (MAPK) inhibitors, PD98059, SP600125 and SB203580, on the pancreatic cancer cell line, PANC-1. Cell proliferation activity was assessed using a 3 H-thymidine incorporation assay, and cell viability was analyzed using an MTT assay. Apoptosis was assayed by flow cytometry and fluorescence microscopy. Protein expression levels in PANC-1 cells were determined by western blotting. The results of this analysis demonstrated that sporamin induced a temporary increase in the phosphorylation of MAPKs, including phosphorylated extracellular signal regulated-kinase 1/2, phosphorylated c-Jun amino-terminal protein kinase 1/2 and phosphorylated p38-MAPK, in a concentration-dependent manner. However, treatment with MAPK inhibitors promoted the inhibition of cell proliferation and viability, and the induction of apoptosis in sporamin-treated PANC-1 cells.In conclusion, the present study demonstrated that MAPK inhibition enhanced the antitumor activity of sporamin in PANC-1 cells. IntroductionPancreatic cancer (PC) is among the most aggressive types of solid tumor, and has the highest rate of cancer-associated mortality worldwide (1). Despite advances in surgical techniques, chemotherapy and radiotherapy, the long-term survival rate for patients with PC has not significantly increased since 1977 (2). Therefore, further research into alternative therapies for PC, which has fewer associated toxicities, is urgently required.Trypsin inhibitors (TIs) are widely distributed in plants and animals, and certain types of TIs have exhibited antitumor activity in several types of tumor cells (3-5). Although no approved therapies directly targeting trypsin directly are currently available, development of novel and more specific TI therapies is underway (3-5). Sporamin, a sweet potato tuber storage protein, is a Kunitz-type TI that has been demonstrated to induce antitumor effects in vitro and in vivo (4,5). Although the role and mechanism of sporamin as an antitumor agent remain unclear, the previous research has indicated that sporamin can mediate the regulation of specific signaling pathways (5). For example, sporamin was demonstrated to inhibit cell growth and induce apoptosis of human tongue cancer cells by downregulating RAC serine/threonine-protein kinase/glycogen synthase kinase-3 signaling (5). However, to the best of our knowledge, the antitumor effects of sporamin in PC have not been previously investigated.Mitogen-activated protein kinases (MAPK) are critically involved in the signaling cascades that govern various critical processes, including cell proliferation, differentiation, apoptosis and survival (6). MAPKs are conserved enzymes that connect cell-surface receptors to their regulatory targets within cells (7). Th...

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