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

Abstract

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 gemcitabineinduced 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.

High-Molecular-Weight Fractions of Spruce and Eucalyptus Lignin as a Perspective Nanoparticle-Based Platform for a Therapy Delivery in Liver Cancer

“…It is important to mention that our data on sorafenib standard therapy on HCC (induction of late apoptosis and necroptosis) is fully in line with previous reports (Lin et al, 2017). The same was also true for gemcitabine which induced early and late apoptosis in our and other studies (Pauwels et al, 2009;Li et al, 2020). Similar to sorafenib, both LNP types induced late apoptosis, whereas sorafenib and E-LNPs also additionally induced necroptosis in the HCC cell line.…”

Aspirin Regulates Gemcitabine Resistance in Pancreatic Cancer via Inhibiting the PI3K/Akt/mTOR Signaling Pathway and Reversing Epithelial-mesenchymal Transition

“…Moreover, aspirin also shows a therapeutic potential through targeted inhibition on tumor growth and angiogenesis [19,20]. Many studies pointed out gemcitabine activation of Akt/mTOR signaling pathway in resistant cells is a key signaling event for gemcitabine resistance, and we suppose aspirin may resensitize resistant cells to gemcitabine by inhibiting this activated pathway [21][22][23]. Considering the above two points, when it comes to combining with aspirin, gemcitabine may be more suitable for research than 5FU, irinotecan, oxaliplatin, taxanes or other chemotherapeutic agents.…”

Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer

“…Moreover, cellular factors related to survival and apoptosis are linked to therapeutic resistance. A recent study showed that gemcitabine resistance is aggravated by an activation of AKT serine/threonine kinase (AKT) signaling; therefore, AKT inhibition augments the efficacy of gemcitabine by activating apoptotic cell death in vitro and in vivo [ 24 ]. In addition, extracellular signal-regulated kinase (ERK) positively regulates the level of anti-apoptosis factors such as B-cell CLL/lymphoma 2 ( BCL2 ), impeding caspase activations [ 25 ].…”