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Role of programmed cell death 4 in diseases: a double-edged sword

Cellular & Molecular Immunology volume 14, pages 884–886 (2017)Cite this article

It has been shown that PDCD4 is often downregulated or virtually eliminated in tumor cells by miR-21, which specifically targets PDCD4 or 5′-CpG methylation in the promotor region, and its forced expression can efficiently inhibit the development and progression of multiple human tumors, including lung, liver, colon, breast, and ovarian cancers and glioma in the brain.1, 13 However, the precise molecular mechanisms remain unclear. As PDCD4 was first identified as a molecule that promotes tumor cell apoptosis in hepatocellular, ovarian, glioma, breast, and gastric tumors, it is reasonable to speculate that the inhibitory function of PDCD4 in tumorigenesis is attributable to its cell apoptotic function. However, unexpectedly, it plays an anti-apoptotic role in HeLa cells by suppressing pro-casp3 mRNA translation, and it has no impact on apoptosis in colon carcinoma. Therefore, several studies have demonstrated that PDCD4 may exert its inhibitory role on tumor cell growth by depressing the transcription of cyclin-dependent kinase 1 through the upregulation of p21 or by directly binding with transcription factor Twist1, which is sequentially followed by the downregulation of the target gene in prostate cancer cells, such as YB-1.10 Our current research proposes the novel possibility that the interference of PDCD4 in autophagy in multiple cell types, both in vitro and in vivo, is responsible for its tumor suppressor activity by suppressing the expression of an essential autophagy-related gene, Atg5, in an eIF4A-dependent manner.5 Furthermore, we suggest that the inflammation-related tumor is also efficiently attenuated by PDCD4 in a dextran sodium sulfate-induced colitis-associated colon cancer model in mice, as PDCD4 deficiency promotes the development of colitis-associated colorectal carcinoma by accelerating the proliferation of epithelial cells during tumorigenesis via the IL-6/STAT3 pathway.14

Notably, it has been recently reported that PDCD4 is also involved in autoimmune inflammatory disease and possesses an pro-inflammatory role by selectively inhibiting protein translation in the immune system given that Pdcd4-deficient mice are resistant to autoimmune encephalomyelitis (EAE) and type 1 diabetes, in which lymphocytes preferentially produce anti-inflammatory cytokines.15 Then, Sheedy et al.,13 indicated in 2010 that lipopolysaccharide (LPS)-induced death can be abolished in Pdcd4-deficient mice by a high level of IL-10 relieving PDCD4 inhibition. Moreover, we demonstrated that Pdcd4-deficient mice are resistant to high fat diet-induced obesity with improved insulin sensitivity and reduced macrophage infiltration and inflammatory cytokine secretion in white adipose tissue (WAT) by inhibiting the expression of liver X receptor (LXR)-α, a master modulator of lipid homeostasis, and its target genes.6 Recently, we presented evidence that PDCD4 can facilitate high fat-induced atherosclerosis by negatively regulating the expression of anti-inflammatory cytokine IL-10 in macrophages in an ERK1/2- and p38-dependent manner, as confirmed by decreased atherosclerotic lesions in Pdcd4(−/−) and Apoe(−/−) mice, which can be partly reversed by blockage of IL-10 with a neutralizing antibody.12 In addition, our research reveals that endogenous PDCD4 can participate in promoting macrophage foam cell formation by suppressing autophagy efflux, whereas with a lack of Pdcd4, oxidized low-density lipoprotein-impaired autophagy efflux can be partly recovered followed by autophagy-mediated lipid breakdown in macrophages, which results in the restraint of macrophage conversion into foam cells. However, PDCD4 also plays a role in inhibitory inflammation in lipopolysaccharide/D-galactosamine-induced acute liver injury and in a dextran sodium sulfate-induced acute colitis mouse model.15 Taken together, there is no doubt that PDCD4 acts as a double-edged sword, suppressing tumors (such as lung cancer, liver cancer, and glioma) and acute inflammation (in acute liver injury and acute colitis), as well as promoting autoimmune or chronic inflammation in EAE, diabetes, high fat-induced obesity, and atherosclerosis simultaneously (Figure 1b).

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Authors and Affiliations

  1. Hematology Department, The Second Hospital of Shandong University, Jinan, China

    Yang Jiang

  2. Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, China

    Yufeng Jia & Lining Zhang

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Jiang, Y., Jia, Y. & Zhang, L. Role of programmed cell death 4 in diseases: a double-edged sword. Cell Mol Immunol 14, 884–886 (2017). https://doi.org/10.1038/cmi.2017.84

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