The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells

Abstract

Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DEAD-box helicase 4 (DDX4), a germline factor and RNA helicase conserved in all multicellular organisms, contributes to increased cell motility and cisplatin-mediated drug resistance in small cell lung cancer (SCLC) cells. Proteomic analysis suggests that DDX4 expression upregulates proteins related to DNA repair and immune/inflammatory response. Consistent with these trends in cell lines, DDX4 depletion compromised in vivo tumor development while its overexpression enhanced tumor growth even after cisplatin treatment in nude mice. Further, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of immune/inflammatory response markers. Taken together, we propose that DDX4 increases SCLC cell survival, by increasing the DNA damage and immune response pathways, especially under challenging conditions such as cisplatin treatment.

Vasa, a regulator of localized mRNA translation on the spindle

“…Importantly, depletion of Vasa/DDX4 from both sea urchin embryonic cells and human SCLC cells results equally in devastating phenotypes such as decreased cell survival and resistance to environmental challenges. [28,37] Taking all these observations together, we propose that Vasa functions in localized translation to aid rapid lineage segregation by controlling protein synthesis with spatial and temporal precision during both symmetric and asymmetric cell divisions. This system might particularly benefit rapidly developing cells that undergo dynamic regulation, such as asymmetric cell divisions and environmental responses.…”

“…These functions are fundamental to cell survival by impacting various downstream pathways, which may explain the devastating phenotype of Vasa‐depleted cells both in embryos and cancer cells. [ 28,37 ]…”

“…Outside of normal development, the human Vasa ortholog DDX4 is also reported to be expressed in several cancer cells, such as epithelial ovarian cancer cells, [34,35] myeloma and leukemia cells, [36] and small cell lung cancer (SCLC) cells. [37] Although its clinical implications are yet to be determined, studies in these established cancer cell lines suggest DDX4 facilitates cell proliferation, motility, and drug resistance in the cell. Further, in SCLC cells, DDX4 depletion appears to reduce general protein synthesis by more than 80%, which is similar to the results of Vasa knockdown in sea urchin embryos.…”

“…However, over 35 DDX family proteins are present, and the multiple functional domains are conserved across the DDX family proteins. [45] Some of the core helicase [37] domain mutants were made in regions not necessarily specific to Vasa, but rather conserved across DDX proteins. [15] Therefore, some of the Supporting this hypothesis, it was recently reported that the core helicase mutants of Vasa had little effect on the oogenesis of Drosophila [46] and the embryonic development of the sea urchin.…”

“…Further, in SCLC cells, DDX4 depletion appears to reduce general protein synthesis by more than 80%, which is similar to the results of Vasa knockdown in sea urchin embryos. [12,28,37] Although more functional evidence from multiple cell types and organisms is needed, current observations cumulatively suggest that Vasa appears to function in general translation rather than regulation of germline-specific mRNAs, at least in somatic cells.…”