2. Academic Validation
  3. BRSK2 plays a role in autophagy and cancer cell growth and survival under nutrient deprivation stress via the PIK3C3 pathway

BRSK2 plays a role in autophagy and cancer cell growth and survival under nutrient deprivation stress via the PIK3C3 pathway

  • Sci Rep. 2025 Nov 19;15(1):40651. doi: 10.1038/s41598-025-24354-4.
Aparna Maiti 1 2,  Alison D Axtman 3,  Rongrong Wu 4,  Lydia J B Redman 4,  Kazuaki Takabe 4,  Aimee B Stablewski 5 6,  Li Yan 7,  Michael J Ciesielski 8 9,  Jianmin Zhang 10,  Sharon S Evans 11,  Pawel Kalinski 11 12,  Nitai C Hait 13 14
Affiliations

Affiliations

  • 1 Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
  • 2 Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA. [email protected].
  • 3 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 5 Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
  • 6 Roswell Park Comprehensive Cancer Center, Gene Targeting and Transgenic Shared Resource, Buffalo, NY, USA.
  • 7 Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, , Buffalo, NY, 14263, USA.
  • 8 Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 9 MimiVax LLC, Buffalo, NY, USA.
  • 10 Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  • 11 Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
  • 12 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
  • 13 Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
  • 14 Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA. [email protected].
PMID: 41258112 DOI: 10.1038/s41598-025-24354-4
Abstract

Macroautophagy/Autophagy is a stress-responsive lysosomal catabolic pathway that promotes cellular homeostasis and tumor cell survival, but its role in breast Cancer progression and metastasis remains unclear. Here, we show that a brain-specific serine/threonine protein kinase, BRSK2, a marker of aggressive metastatic disease in breast Cancer patients, is crucial in regulating Autophagy. BRSK2 is overexpressed in aggressive Cancer and is associated with reduced disease-specific survival. BRSK2 also regulates basal Autophagy and activates Akt, STAT3, and NF-κB-mediated Cancer cell survival pathways. In addition, BRSK2 overexpression increases the levels of inflammatory cytokines and chemokines in breast Cancer cells. Downregulation of BRSK2 using specific siRNAs or the BRSK2 kinase small-molecule inhibitor GW296115 markedly reduced nutrient-deprivation stress-mediated Autophagy, cell growth, and metastatic potential, and enhanced breast Cancer cell Apoptosis. Endogenous BRSK2 is associated with the Vps34-class III PI3K-Beclin-1-ATG14 Autophagy signaling complexes that could protect Cancer cells from nutrient-deprivation stress. Our findings demonstrate the key role of the BRSK2-mediated protective Autophagy and cell growth and survival under nutrient deprivation stress via survival signals, e.g., PI3K/Akt or STAT3-NF-kB, in aggressive breast Cancer cells.

Keywords

Autophagy; BRSK2; Breast cancer; Cell survival; Nutrient-deprivation stress.

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