Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway

Abstract

KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation.

Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA

“…This would provide a ‘decision point’ for entry into apoptosis, which is triggered either by a stoichiometric excess of NOXA over MCL1, or upon activation of additional pro-apoptotic BH3 proteins by compounds such as ABT-737. In support of this, concomitant NOXA and MCL1 upregulation is observed in MYC-driven leukemias [ 49 ], and following activation of RAS in epithelial cells [ 50 ]. Furthermore, despite concomitant upregulation of NOXA and MCL1, squamous cell carcinomas retain sensitivity to ABT-737 due to an increased NOXA:MCL1 ratio [ 36 ].…”

Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling

“…In addition, ERK‐dependent up‐regulation of NOXA by mutant KRAS is also able to sensitise premalignant human epithelial cells to the combination of a SMAC mimetic (SM83) and camptothecin (CPT). However, this effect on NOXA and sensitisation to SM83/CPT is lost in malignant colorectal cancer cells with KRAS mutations due to aberrant activation of PI3K‐dependent survival signalling . This effect was attributed to PKB/AKT activation using the tricyclic nucleoside Triciribine, an inhibitor of DNA synthesis that has also shown potent activity against PKB/AKT, but was not confirmed using PKB/AKT‐specific RNAi.…”

“…In contrast to the preceding examples, the BH3‐only protein NOXA is very clearly induced rather than repressed by ERK1/2 signalling. For example, activation of ERK1/2 by activated mutant HRAS drives NOXA mRNA and protein expression, whereas inhibition of ERK1/2 signalling in tumour cells with pathway deregulation, such as BRAF 600E in melanoma, reduces NOXA levels . In terms of mechanism it appears that ERK1/2 signalling drives NOXA transcription via CREB; a CREB‐binding site in the NOXA 5′‐UTR was required for BRAF 600E ‐driven expression of a NOXA ‐driven reporter construct while CREB phosphorylation was commensurate with NOXA expression .…”

Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia

“…It has been previously reported that Noxa expresses in colorectal cancers, malignant melanomas and ameloblastomas [36,37,38,39], and that it is involved in the mechanism of action of the anticancer agents bortezomib and pemetrexed [40,41,42,43,44,45,46,47]. However, the expression of Noxa in mesothelioma cells has so far not been reported.…”

“…In the literature, it has been reported that oncogenic activation of MEK/ERK drives Noxa expression to promote autophagy, and Noxa displays indirect antiapoptosis activity in malignant melanoma [38]. Oncogenic activation of MEK/ERK drives Noxa expression in colorectal cancer, but the activated PI3K/AKT pathway counterbalances Noxa, leading to apoptotic changes [39]. It is possible that similar mechanism acts in the mesothelioma.…”