Abstract
Non-small cell lung cancer (NSCLC) accounts for 80–85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent inhibition of PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, IKKα ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through the activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.
| Original language | English (US) |
|---|---|
| Article number | 33 |
| Journal | npj Precision Oncology |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Bibliographical note
Funding Information:This work was supported by a Research Scholar Grant RSG-21-034-01-TBG from the American Cancer Society, a Windfeldt Cancer Research Award, the Elsa U. Pardee Foundation, and The Hormel Foundation (to L.H.H.) as well as the Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award (to S.K.A.). We thank Sam Hagan and Brianna Kriesel for providing assistance with culturing cells, immunoblotting studies, and plasmid preparations. We thank Naomi Ruff for suggesting helpful manuscript revisions. We are grateful to Wael El-Rifai for sharing DARPP-32 plasmids, Georgiy Aslanidi for sharing expression plasmids, and Pasi A. Jänne, Aaron N. Hata, and Anthony C. Faber for generously providing NSCLC cells. We thank The Hormel Institute and its staff for administrative, shared equipment, animal facility, and institutional support. We appreciate the data acquisition assistance provided by Todd Schuster and Tanner Conway.
Funding Information:
This work was supported by a Research Scholar Grant RSG-21-034-01-TBG from the American Cancer Society, a Windfeldt Cancer Research Award, the Elsa U. Pardee Foundation, and The Hormel Foundation (to L.H.H.) as well as the Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award (to S.K.A.). We thank Sam Hagan and Brianna Kriesel for providing assistance with culturing cells, immunoblotting studies, and plasmid preparations. We thank Naomi Ruff for suggesting helpful manuscript revisions. We are grateful to Wael El-Rifai for sharing DARPP-32 plasmids, Georgiy Aslanidi for sharing expression plasmids, and Pasi A. Jänne, Aaron N. Hata, and Anthony C. Faber for generously providing NSCLC cells. We thank The Hormel Institute and its staff for administrative, shared equipment, animal facility, and institutional support. We appreciate the data acquisition assistance provided by Todd Schuster and Tanner Conway.
Publisher Copyright:
© 2023, The Author(s).
PubMed: MeSH publication types
- Journal Article
