Conditional Expression of Oncogenic C-RAF in Mouse Pulmonary Epithelial Cells Reveals Differential Tumorigenesis and Induction of Autophagy Leading to Tumor Regression

Abstract

Here we describe a novel conditional mouse lung tumor model for investigation of the pathogenesis of human lung cancer. On the basis of the frequent involvement of the Ras-RAF-MEK-ERK signaling pathway in human non-small cell lung carcinoma (NSCLC), we have explored the target cell availability, reversibility, and cell type specificity of transformation by oncogenic C-RAF. Targeting expression to alveolar type II cells or to Clara cells, the two likely precursors of human NSCLC, revealed differential tumorigenicity between these cells. Whereas expression of oncogenic C-RAF in alveolar type II cells readily induced multifocal macroscopic lung tumors independent of the developmental state, few tumors with type II pneumocytes features and incomplete penetrance were found when targeted to Clara cells. Induced tumors did not progress and were strictly dependent on the initiating oncogene. Deinduction of mice resulted in tumor regression due to autophagy rather than apoptosis. Induction of autophagic cell death in regressing lung tumors suggests the use of autophagy enhancers as a treatment choice for patients with NSCLC.

High Levels of miR-7-5p Potentiate Crizotinib-Induced Cytokilling and Autophagic Flux by Targeting RAF1 in NPM-ALK Positive Lymphoma Cells

“…To start, we looked in the literature for experimentally validated miR-7-5p targets and then narrowed our research to the ones described to participate in the regulation of the autophagy process. The RAF1 kinase mRNA was an interesting candidate as it fulfilled these criteria both as a target of miR-7-5p, as described in melanoma cells [ 59 ], and as a regulator of autophagy, as previously reported [ 60 , 61 ].…”

“…Of interest, an enhanced and detrimental autophagy was similarly observed following an ALKBH5 silencing/miR-7-5p increase and subsequent downregulation of the EGFR/Akt/mTOR axis in epithelial ovarian cancer cells [58]. In the literature, RAF1 inhibition was shown to induce autophagy and tumor regression in a conditional mouse model for RAF1-induced lung tumorigenesis [61]. Conversely, Kinsey et al recently demonstrated that the RAF1/MEK/ERK pathway inhibition elicited protective autophagy in pancreatic ductal adenocarcinoma cells, through the activation of the LKB1/AMPK/ULK1 signaling axis [83].…”

“…In the literature, RAF1 inhibition was shown to induce autophagy and tumor regression in a conditional mouse model for RAF1-induced lung tumorigenesis [ 61 ]. Conversely, Kinsey et al recently demonstrated that the RAF1/MEK/ERK pathway inhibition elicited protective autophagy in pancreatic ductal adenocarcinoma cells, through the activation of the LKB1/AMPK/ULK1 signaling axis [ 83 ].…”

Inhibition of atypical protein kinase Cι induces apoptosis through autophagic degradation of β‐catenin in esophageal cancer cells

“…Autophagy is believed to have both pro‐ and anti‐oncogenic effects on tumor cells . Disrupted Beclin 1 in mice enhances the incidence of several types of cancers in mice, suggesting a suppressive role for autophagy , and autophagy inducers are widely used to kill cancer cells ; Evidence also suggests that autophagy plays a protective role in some cancer cells . Whether autophagy inducers suppress cancer cells may depend on the individual inducers used or the context of protein profiles within the cells.…”

C-Raf deficiency leads to hearing loss and increased noise susceptibility

“…Although the three RAF proteins can phosphorylate ERK, B-RAF is the most efficient one, and therefore, it plays a central role in the physiopathology of cell proliferation [ 15 ]. The first Raf gene was isolated from retroviruses [ 16 ] and was found to be closely associated with cancer [ 17 ]. C-RAF is also ubiquitous [ 18 ] and plays a role in cell survival [ 19 ].…”