F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptotic death of human cancer cells while sparing normal human cells. Although TRAIL holds great promise as a potential anticancer agent, some tumors develop resistance to TRAIL. Previously, we have shown that the activator protein 1 (AP-1) family member, c-Fos, is an important modulator of apoptosis. Although F- box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, c-Jun, its role in mediating apoptotic pathways has not been previously investigated. Here, we report that FBXL10 is a transcriptional repressor of c-Fos and a target gene of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-p65 in human cancers. We demonstrate that FBXL10 is an important anti-apoptotic molecule, which directly binds and represses c-Fos promoter in order for cancer cells to resist TRAIL-induced apoptosis. FBXL10 indirectly regulates c-FLIP(L) levels via c-Fos-dependent pathways. Silencing of FBXL10 sensitizes resistant cells to TRAIL, while, overexpression of FBXL10 represses TRAIL-induced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-κB-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-κB signaling. Taken together, we find a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic-related pathway that involves NF-κB/FBXL10/c-Fos/c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies.

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Abbreviations

FBXL10:

F- box protein 10

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

AP-1:

activator protein 1

BS:

binding site

NF-κB:

nuclear factor kappa-light-chain-enhancer of activated B cells

Lexa:

lexatumumab

LPS:

lipopolysaccharides

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Acknowledgements

This work was partially funded by support from the Edwin Beer Fellowship–New York Academy of Medicine to AFO.

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Correspondence to A F Olumi.

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The authors declare no conflict of interest.

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Edited V Dixit

Supplementary Information accompanies the paper on Cell Death and Differentiation website

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Keywords

  • c-FLIP
  • c-Fos
  • FBXL10
  • NF-κB
  • TRAIL
  • apoptosis

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