Preprint Article Version 1 This version is not peer-reviewed

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Version 1 : Received: 20 October 2017 / Approved: 24 October 2017 / Online: 24 October 2017 (05:43:16 CEST)

How to cite: Jeong, S.; Jing, K.; Shin, S.; Kim, S.; Han, S.; Yoo, Y.; Jeon, Y.; Heo, J.; Kweon, G.; Park, S.; Park, J.; Lim, K. Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer. Preprints 2017, 2017100157 (doi: 10.20944/preprints201710.0157.v1). Jeong, S.; Jing, K.; Shin, S.; Kim, S.; Han, S.; Yoo, Y.; Jeon, Y.; Heo, J.; Kweon, G.; Park, S.; Park, J.; Lim, K. Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer. Preprints 2017, 2017100157 (doi: 10.20944/preprints201710.0157.v1).

Abstract

Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was associated with downregulation of Hh signaling, and knockdown of SIRT6 resulted in augmentation of Hh signaling. Pretreatment of NSCLC cells with a Smoothened agonist prevented DHA-induced decreases in the levels of Hh signaling proteins and increases in cleaved PARP levels. Moreover, endogenous production of ω3-PUFAs in PC9 cells via fat-1 expression resulted in elevated SIRT6 levels and reduced levels of Hh signaling molecules, including Gli, following DHA treatment. Overall, these results implicate that ω3-PUFAs induce apoptosis by downregulating Hh signaling via SIRT6 activation in human EGFR mutant NSCLC cells. These findings suggest that ω3-PUFAs potentially represent an effective therapy for the chemoprevention and treatment of NSCLC.

Subject Areas

docosahexaenoic acid; apoptosis; SIRT6; Hedgehog signaling; non-small cell lung cancer cells

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