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

Noyes, C.; Kitajima, S.; Li, F.; Suita, Y.; Miriyala, S.; Isaac, S.; Ahsan, N.; Knelson, E.; Vajdi Hoojghan, A.; Tani, T.; Thai, T.; Xu, D.; Murai, J.; Tapinos, N.; Takahashi, C.; Barbie, D.; Yajima, M.

doi:10.1101/2022.04.22.489111

bioRxiv · 10.1101/2022.04.22.489111

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

Noyes, C.·Kitajima, S.·Li, F.·Suita, Y.·Miriyala, S.·Isaac, S.·Ahsan, N.·Knelson, E.·Vajdi Hoojghan, A.·Tani, T.·Thai, T.·Xu, D.·Murai, J.·Tapinos, N.·Takahashi, C.·Barbie, D.·Yajima, M.

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Abstract

Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DDX4, a germline factor and RNA helicase conserved in all multicellular organisms, contributes to epithelial mesenchyme transition (EMT)-like features and cisplatin resistance in small cell lung cancer (SCLC) cells. DDX4 depletion in H69AR and SHP77 cell lines decreased motility and resistance to cisplatin, whereas its overexpression increased these features. Proteomic analysis suggests that DDX4 upregulates metabolic protein expression related to DNA repair and immune/inflammatory response, suggesting its fundamental function may be in regulating cellular metabolism. 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. Although the DDX4 expression level in somatic tumors is generally low compared to that in the germline, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of EMT and cisplatin resistance markers. Taken together, we conclude that DDX4 influences the survival of SCLC patients by altering cellular metabolism in response to environmental cues such as drug treatments. This fundamental function of DDX4 as a germline factor might be applicable in other cancer types that express DDX4 and may serve as a key to combat specific tumors that are highly resistant to treatments. HighlightsO_LIDDX4 contributes to cellular motility and drug resistance in SCLC cells. C_LIO_LIDDX4-overexpression globally alters the proteome and suppresses cytokine production. C_LIO_LIDDX4 promotes tumorigenesis and drug resistance in vitro and in vivo. C_LIO_LIDDX4 expression correlates with survival in SCLC patients and with immune/inflammatory response both in cell lines and patient samples. C_LI

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Noyes, C., Kitajima, S., Li, F., Suita, Y., Miriyala, S., Isaac, S., Ahsan, N., Knelson, E., Vajdi Hoojghan, A., Tani, T., Thai, T., Xu, D., Murai, J., Tapinos, N., Takahashi, C., Barbie, D., Yajima, M.. 2022-04-22. The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells. https://doi.org/10.1101/2022.04.22.489111

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