Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling

Dinesh Thapa; Shih Bo Huang; Amanda R. Muñoz; Xiaoyu Yang; Roble G. Bedolla; Chia Nung Hung; Chun Liang Chen; Tim H.M. Huang; Michael A. Liss; Robert L. Reddick; Hiroshi Miyamoto; Addanki P. Kumar; Rita Ghosh

doi:10.1038/s42003-019-0720-z

Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling

Dinesh Thapa, Shih Bo Huang, Amanda R. Muñoz, Xiaoyu Yang, Roble G. Bedolla, Chia Nung Hung, Chun Liang Chen, Tim H.M. Huang, Michael A. Liss, Robert L. Reddick, Hiroshi Miyamoto, Addanki P. Kumar, Rita Ghosh

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

NAD[P]H:quinone oxidoreductase 1 (NQO1) regulates cell fate decisions in response to stress. Oxidative stress supports cancer maintenance and progression. Previously we showed that knockdown of NQO1 (NQO1^low) prostate cancer cells upregulate pro-inflammatory cytokines and survival under hormone-deprived conditions. Here, we tested the ability of NQO1^low cells to form tumors. We found NQO1^low cells form aggressive tumors compared with NQO1^high cells. Biopsy specimens and circulating tumor cells showed biochemical recurrent prostate cancer was associated with low NQO1. NQO1 silencing was sufficient to induce SMAD-mediated TGFβ signaling and mesenchymal markers. TGFβ treatment decreased NQO1 levels and induced molecular changes similar to NQO1 knockdown cells. Functionally, NQO1 depletion increased migration and sensitivity to oxidative stress. Collectively, this work reveals a possible new gatekeeper role for NQO1 in counteracting cellular plasticity in prostate cancer cells. Further, combining NQO1 with TGFβ signaling molecules may serve as a better signature to predict biochemical recurrence.

Original language	English (US)
Article number	12
Journal	Communications Biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0720-z
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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Thapa, D., Huang, S. B., Muñoz, A. R., Yang, X., Bedolla, R. G., Hung, C. N., Chen, C. L., Huang, T. H. M., Liss, M. A., Reddick, R. L., Miyamoto, H., Kumar, A. P., & Ghosh, R. (2020). Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling. Communications Biology, 3(1), Article 12. https://doi.org/10.1038/s42003-019-0720-z

Thapa, D, Huang, SB, Muñoz, AR, Yang, X, Bedolla, RG, Hung, CN, Chen, CL , Huang, THM, Liss, MA, Reddick, RL, Miyamoto, H, Kumar, AP & Ghosh, R 2020, 'Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling', Communications Biology, vol. 3, no. 1, 12. https://doi.org/10.1038/s42003-019-0720-z

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title = "Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling",

abstract = "NAD[P]H:quinone oxidoreductase 1 (NQO1) regulates cell fate decisions in response to stress. Oxidative stress supports cancer maintenance and progression. Previously we showed that knockdown of NQO1 (NQO1low) prostate cancer cells upregulate pro-inflammatory cytokines and survival under hormone-deprived conditions. Here, we tested the ability of NQO1low cells to form tumors. We found NQO1low cells form aggressive tumors compared with NQO1high cells. Biopsy specimens and circulating tumor cells showed biochemical recurrent prostate cancer was associated with low NQO1. NQO1 silencing was sufficient to induce SMAD-mediated TGFβ signaling and mesenchymal markers. TGFβ treatment decreased NQO1 levels and induced molecular changes similar to NQO1 knockdown cells. Functionally, NQO1 depletion increased migration and sensitivity to oxidative stress. Collectively, this work reveals a possible new gatekeeper role for NQO1 in counteracting cellular plasticity in prostate cancer cells. Further, combining NQO1 with TGFβ signaling molecules may serve as a better signature to predict biochemical recurrence.",

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doi = "10.1038/s42003-019-0720-z",

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AU - Thapa, Dinesh

AU - Huang, Shih Bo

AU - Muñoz, Amanda R.

AU - Yang, Xiaoyu

AU - Bedolla, Roble G.

AU - Hung, Chia Nung

AU - Chen, Chun Liang

AU - Huang, Tim H.M.

AU - Liss, Michael A.

AU - Reddick, Robert L.

AU - Miyamoto, Hiroshi

AU - Kumar, Addanki P.

AU - Ghosh, Rita

PY - 2020/12/1

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N2 - NAD[P]H:quinone oxidoreductase 1 (NQO1) regulates cell fate decisions in response to stress. Oxidative stress supports cancer maintenance and progression. Previously we showed that knockdown of NQO1 (NQO1low) prostate cancer cells upregulate pro-inflammatory cytokines and survival under hormone-deprived conditions. Here, we tested the ability of NQO1low cells to form tumors. We found NQO1low cells form aggressive tumors compared with NQO1high cells. Biopsy specimens and circulating tumor cells showed biochemical recurrent prostate cancer was associated with low NQO1. NQO1 silencing was sufficient to induce SMAD-mediated TGFβ signaling and mesenchymal markers. TGFβ treatment decreased NQO1 levels and induced molecular changes similar to NQO1 knockdown cells. Functionally, NQO1 depletion increased migration and sensitivity to oxidative stress. Collectively, this work reveals a possible new gatekeeper role for NQO1 in counteracting cellular plasticity in prostate cancer cells. Further, combining NQO1 with TGFβ signaling molecules may serve as a better signature to predict biochemical recurrence.

AB - NAD[P]H:quinone oxidoreductase 1 (NQO1) regulates cell fate decisions in response to stress. Oxidative stress supports cancer maintenance and progression. Previously we showed that knockdown of NQO1 (NQO1low) prostate cancer cells upregulate pro-inflammatory cytokines and survival under hormone-deprived conditions. Here, we tested the ability of NQO1low cells to form tumors. We found NQO1low cells form aggressive tumors compared with NQO1high cells. Biopsy specimens and circulating tumor cells showed biochemical recurrent prostate cancer was associated with low NQO1. NQO1 silencing was sufficient to induce SMAD-mediated TGFβ signaling and mesenchymal markers. TGFβ treatment decreased NQO1 levels and induced molecular changes similar to NQO1 knockdown cells. Functionally, NQO1 depletion increased migration and sensitivity to oxidative stress. Collectively, this work reveals a possible new gatekeeper role for NQO1 in counteracting cellular plasticity in prostate cancer cells. Further, combining NQO1 with TGFβ signaling molecules may serve as a better signature to predict biochemical recurrence.

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Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling

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