Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties

Abstract

TP53 is a master regulator of many signaling and apoptotic pathways involved in: aging, cell cycle progression, gene regulation, growth, apoptosis, cellular senescence, DNA repair, drug resistance, malignant transformation, metastasis, and metabolism. Most pancreatic cancers are classified as pancreatic ductal adenocarcinomas (PDAC). The tumor suppressor gene TP53 is mutated frequently (50–75%) in PDAC. Different types of TP53 mutations have been observed including gain of function (GOF) point mutations and various deletions of the TP53 gene resulting in lack of the protein expression. Most PDACs have point mutations at the KRAS gene which result in constitutive activation of KRas and multiple downstream signaling pathways. It has been difficult to develop specific KRas inhibitors and/or methods that result in recovery of functional TP53 activity. To further elucidate the roles of TP53 in drug-resistance of pancreatic cancer cells, we introduced wild-type (WT) TP53 or a control vector into two different PDAC cell lines. Introduction of WT-TP53 increased the sensitivity of the cells to multiple chemotherapeutic drugs, signal transduction inhibitors, drugs and nutraceuticals and influenced key metabolic properties of the cells. Therefore, TP53 is a key molecule which is critical in drug sensitivity and metabolism of PDAC.

Inhibition of Axl: Enhancement of Erlotinib Cytotoxicity in Human Pancreatic Cancer Cells

“…EGFR is a member of the ErbB receptor family [10] and is highly expressed in a variety of tumour cells including pancreatic cancer [11] . In pancreatic cancer cells, when EGFR binds to the related ligands, it phosphorylates tyrosine residues in the cells, which in turn activates two important downstream signalling pathways, Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K)/AKT, thus playing a role in regulating cell proliferation, survival and migration [12][13][14] . ERK1/2 and AKT are key enzymatic proteins in these two signalling pathways.…”

Ultrasound-targeted microbubble destruction improves the suppression and magnetic resonance imaging of pancreatic cancer with polyethyleneimine nanogels

“…Four experimental groups were used: control group (mock), gemcitabine alone group (G), gemcitabine and siRNA nanohydrogel group (PEI), gemcitabine and siRNA nanohydrogel + UTMD group (PEI+UTMD). First, 3×10 3 PCCs from each of the different treatment groups were plated in wells of a 96-well plate. After incubating for 0, 24, 48, 72, or 96 hours, 10 μL of CCK-8 solution was added to each well.…”

“…Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant type of cancer with poor prognosis and strong resistance to the first-line chemotherapy drug gemcitabine 1 - 3 . The five-year survival rate of PDAC patients is less than 5%, with a median survival time of less than six months 4 , 5 .…”

The role of metabolic reprogramming in pancreatic cancer chemoresistance

“…P53, the gene product of TP53, mediates increased glycolysis by TP53-induced glycolysis and apoptosis regulator (TIGAR). Introduction of WT-TP53 improves the sensitivity of PC cells to multiple chemotherapeutic agents, including EGFR/Ras/Raf/MEK and PI3K/mTORC1/GSK-3 pathway inhibitors, and affects crucial metabolic properties of the cells ( McCubrey et al, 2022 ).…”