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 journalArticle

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.

Original languageEnglish (US)
Article number12
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - Dec 1 2020

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NAD(P)H dehydrogenase (quinone)
prostatic neoplasms
NAD
Plasticity
Tumors
Prostatic Neoplasms
Oxidoreductases
Oxidative stress
Cells
Neoplasms
Biopsy
neoplasms
cells
oxidative stress
Hormones
Oxidative Stress
Cytokines
Molecules
Circulating Neoplastic Cells
biopsy

ASJC Scopus subject areas

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

Cite this

Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling. / Thapa, Dinesh; Huang, Shih Bo; Muñoz, Amanda R.; Yang, Xiaoyu; Bedolla, Roble G.; Hung, Chia Nung; Chen, Chun Liang; Huang, Tim H.M.; Liss, Michael A.; Reddick, Robert L.; Miyamoto, Hiroshi; Kumar, Addanki P.; Ghosh, Rita.

In: Communications Biology, Vol. 3, No. 1, 12, 01.12.2020.

Research output: Contribution to journalArticle

Thapa, Dinesh ; Huang, Shih Bo ; Muñoz, Amanda R. ; Yang, Xiaoyu ; Bedolla, Roble G. ; Hung, Chia Nung ; Chen, Chun Liang ; Huang, Tim H.M. ; Liss, Michael A. ; Reddick, Robert L. ; Miyamoto, Hiroshi ; Kumar, Addanki P. ; Ghosh, Rita. / Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling. In: Communications Biology. 2020 ; Vol. 3, No. 1.
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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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