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The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells

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Abstract

Raf-1 has an important role in cellular antiapoptosis. So far, there is no solid evidence that shows that Raf-1 mutation is associated with cancer development. In the course of further study of Raf-1 signaling, we have reported that Raf-1 hyperphosphorylation inhibits its kinase activity toward its downstream mitogen-activated protein kinase kinase 1/2 (MEK1/2) and proposed a model for negative feedback regulation of Raf-1. Here, we show that there is no hyperphosphorylation in some cancer cells, which results in increased kinase activity and enhances the antiapoptotic ability. Inhibition of either Raf-1 or ALG-2 (apoptosis-linked gene 2) expression results in apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase (ASK1/JNK) signaling activation, and cell sensitivity to chemotherapeutic reagents, indicating that inhibition of ASK1/JNK apoptotic signaling by Raf-1 is mediated by ALG-2. A previous report indicated that extracellular signal-regulated kinase 1/2 (ERK1/2) were responsible for Raf-1 hyperphosphorylation. However, our evidence shows that when ERK1/2 are activated and the Raf-1 gene is not mutated, Raf-1 is not hyperphosphorylated in these cells, indicating that ERK1/2 are not responsible for the Raf-1 hyperphosphorylation in these cancer cell lines. Surprisingly, we also found that Raf-1 is not a necessary kinase for MEK1/2 activation under normal tissue culture conditions, but is required for MEK1/2 activation under apoptosis-inducing conditions. Our research demonstrates that although Raf-1 gene is not mutated, an abnormality of Raf-1 kinase feedback regulation enhances its antiapoptotic function, and Raf-1 can still be a pharmaceutical target to increase chemotherapy or radiotherapy sensitivity in these cancer cells.

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Acknowledgements

This work was financially supported by Sichuan Scientific and Technology Department Basic Research Fund (2015JY0011) (to CC) and Sichuan Cancer Hospital Research Fund (to CC).

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Author notes

  1. S Q Ma and B R Cao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China

    S Q Ma, B R Cao, H Zhang, L P Luo, Y Ren & C M Chen

  2. Department of Gynecological Oncology, Sichuan Cancer Hospital/Institute, Chengdu, China

    T Hu

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  1. S Q Ma
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  2. B R Cao
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  3. H Zhang
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Correspondence to C M Chen.

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Ma, S., Cao, B., Zhang, H. et al. The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells. Oncogene 36, 2014–2022 (2017). https://doi.org/10.1038/onc.2016.384

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