PROM2 promotes gemcitabine chemoresistance via activating the Akt signaling pathway in pancreatic cancer

In recent years, the deoxycytidine analogue gemcitabine (2′,2′,-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment. A cell membrane protein called PROM2 promotes the resistance of pancreatic cancer to the anti-cancer drug gemcitabine, suggesting PROM2 and the molecular signaling pathway it stimulates could be targeted by new treatments. Researchers in China led by Jian Sun at Sun Yat-Sen University, Guangzhou, investigated the role of PROM2 in cultured human pancreatic cancer cells and in a mouse model of pancreatic cancer. Production and activity of PROM2 were increased in cancer cells, leading to increased resistance to gemcitabine. The researchers found that PROM2’s promotion of gemcitabine resistance was linked to its ability to bind to another protein called Akt. This interaction stimulates the Akt signaling pathway, sustaining cancer cells. Combining gemcitabine therapy with an Akt pathway inhibitor restored cancer cell sensitivity to gemcitabine, revealing a potential approach to developing drugs to overcome gemcitabine resistance.