Abstract
The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent type of pancreatic cancer that accounts for about 85% of pancreatic tumors
70% of whom are between the ages of 55 and84 and mostly men [2,3], the mutation in the oncogene KRAS gene, which plays a role in the development of PDAC, activates the Cyclin-Dependent Kinases (CDK) and the mTOR signaling pathway associated with increased cell survival [4,5]
We found that increasing concentrations of LY2835219 and PD-0332991 decreased cell viability in a dose-dependent manner in PANC-1 and MIA PaCa-2 cells (Figure 1A,B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent type of pancreatic cancer that accounts for about 85% of pancreatic tumors. 70% of whom are between the ages of 55 and and mostly men [2,3], the mutation in the oncogene KRAS (proto-oncogene, GTPase) gene, which plays a role in the development of PDAC, activates the Cyclin-Dependent Kinases (CDK) and the mTOR signaling pathway associated with increased cell survival [4,5]. Molecular profiling studies have shown that KRAS mutations and the CDK inhibitor 2A (CDKN2A or INK 4A/ARF), a tumor suppressor gene, is inactivated in PDAC. The PI3K/AKT/mTOR pathway plays a critical role in controlling cell growth, proliferation, migration, and metabolism [18,19,20]. AMPK inhibits the PI3K/AKT/mTOR signaling to reduce cell proliferation through the attenuation of Cyclin D, CDK4, and CDK6 levels [22,23,24]. The continuous activation of the cell cycle and related signaling pathways has enabled the use of CDK inhibitors as an effective therapeutic agents in cancer treatment [27]
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