Abstract
Cellular prion protein (PrPC), the infective agent of transmissible spongiform encephalopathies, is thought to be related to several cellular physiological and physiopathological processes. We have previously reported that PrPC participates in multi-drug-resistance of gastric cancer. As the salient ligand molecule of PrP for participating in internalization and propagation of the scrapie form of prion protein (PrPSc), 37 kDa laminin receptor precursor protein (37LRP) shared the same gene coding sequence of MGr1-Ag, another protein previously found to be involved in multi-drug-resistance of gastric cancer in our lab. In the present study, we explored whether MGr1-Ag/37LRP contributed to PrPC mediated multi-drug-resistance in gastric cancer. Immunohistochemical staining showed similar expression patterns of MGr1-Ag/37LRP and PrPC in gastric cancer tissue serial sections. Western blot and immunohistochemistry also demonstrated correlative expression of MGr1-Ag/37LRP and PrPC in gastric cancer cell lines. Interaction between MGr1-Ag/37LRP and PrPC in gastric cancer cell lines and gastric cancer tissues were verified by immunofluorescence and co-immunoprecipitation. Furthermore, knockdown of MGr1-Ag/37LRP significantly attenuated PrPC induced multi-drug-resistance by sensitizing drug-induced apoptosis through inhibition of AKT activation. In conclusion, MGr1-Ag/37LRP may interact with PrPC and promote the PrPC induced multi-drug-resistance in gastric cancer through PI3K/AKT pathway. The current study elucidates the mechanism of how PrPC triggers intracellular signaling cascade resulting in multi-drug-resistance phenotype and provides a novel candidate molecular target against gastric cancer.
Highlights
PrPC is the cellular form of prion protein, which is generally considered to be the infective agent of transmissible spongiform encephalopathies both in human and animals [1]
We explored whether MGr1-Ag/37 kDa laminin receptor precursor protein (37LRP) contributed to PrPC mediated multi-drug-resistance in gastric cancer
We found that PrPC and MGr1-Ag/37LRP are involved in hypoxiamediated gastric cancer MDR
Summary
PrPC is the cellular form of prion protein, which is generally considered to be the infective agent of transmissible spongiform encephalopathies both in human and animals [1]. The physiological role of PrPC still remains elusive. The putative roles of PrPC are thought to be related to a lot of physiological and physiopathologic processes including cell adhesion, cell growth and proliferation, cell death, signal transduction, as well as cholesterol, iron, zinc and copper metabolism [3,4,5,6,7]. Our previously studies showed that PrPC is highly expressed in gastric cancer tissues and gastric cancer cell lines and has notable effects on tumorigenesis and metastasis of gastric cancer [8, 9]. We previously reported that PrPC is related to multi-drug-resistance with aberrant high expression in Adriamycin(ADR)-resistant gastric adenocarcinoma cell line SGC7901/ADR and Vincristine(VCR)-resistant cell line SGC7901/VCR, [10] which displayed cross-resistance to other anticancer drugs [11]. Previous data demonstrated that ectopic overexpression of PrPC might induce gastric cancer cells to display significantly enhanced resis tance to chemical therapeutic drugs [12]
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