Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals

Abstract

Mutations at the TP53 gene are readily detected (approximately 50-75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-* Corresponding author.

TP53/miR-34a-associated signaling targets SERPINE1 expression in human pancreatic cancer

“…The MIA-PaCa-2+WT-TP53 cells were more sensitive to the chemotherapeutic drugs compared to MIA-PaCa-2+pLXSN cells (Supplementary Figure 1). Similar results have been reported by earlier studies [23,[31][32][33]. The above results authenticate the physiological effects of expressing different forms of TP53 and associated cell signaling.…”

“…MIA-PaCa-2 cells were purchased from the ATCC (Rockville, MD, USA). Cells were cultured in medium containing 5% fetal bovine serum (FBS) purchased from (Atlanta Biologicals, Atlanta, GA, USA) as described in [33]. Tissue culture medium (Dulbecco's modified Eagles medium, DMEM), antibiotics containing l-glutamine and trypsin were obtained from Invitrogen (Carlsbad, CA, USA).…”

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

“…Two important kinase cascades are the Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1 pathways. They are often involved in regulation of cell growth and their aberrant regulation is often implicated in cancer [ 45 – 47 ]. Restoration of WT-TP53 activity in MIA-PaCa-2 cells increased the sensitivity to the MEK1 inhibitor PD0325901 3.3-fold.…”

MicroRNA‑190b expression predicts a good prognosis and attenuates the malignant progression of pancreatic cancer by targeting MEF2C and TCF4

“…The percentage of positive cells was defined as follows: 0, <5%; 1, 5-25%; 2, 26-50%; and 3, 51-100%. MEF2C and TCF4 staining scores were classified as low expression (0-1) or high expression (2)(3)(4)(5)(6).…”

“…Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignant tumor encountered worldwide (1)(2)(3)(4)(5). Although extensive research studies have investigated diagnostic biomarkers for PDAC, detailed analyses of the underlying molecular mechanisms are still needed for the development of targeted therapies (1).…”