RAB33A promotes metastasis via RhoC accumulation through non-canonical autophagy in cervical cancer

Cell Death Dis. 2025 Feb 25;16(1):130. doi: 10.1038/s41419-025-07455-w.

Abstract

Cervical cancer metastasis is characterized by the systemic spread of tumor cells. However, the underlying mechanism remains incompletely understood. Herein, we demonstrate that RAB33A promoted metastasis by enhancing RhoC accumulation and that higher RAB33A expression predicted poorer prognosis in patients with cervical cancer. Mechanistically, RhoC typically degraded via canonical autophagy due to the binding of two LIR motifs (LC3 interaction region) in RhoC to LC3; however, RAB33A induced non-canonical autophagy, resulting in RhoC stabilization, which facilitated pseudopodia formation and consequently cervical cancer metastasis. The fusion of RAB33A-induced autophagosomes with lysosomes was impaired, as RAB33A inactivated RAB7 by interacting with TBC1D2A, a GTPase-activating protein that targets RAB7. Our findings reveal a pivotal role of the RAB33A-RhoC axis in cervical cancer metastasis, indicating that RhoC inhibitors may be beneficial for treating cervical cancer patients with high levels of RAB33A.

MeSH terms

  • Animals
  • Autophagy* / genetics
  • Cell Line, Tumor
  • Female
  • GTPase-Activating Proteins / metabolism
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Uterine Cervical Neoplasms* / genetics
  • Uterine Cervical Neoplasms* / metabolism
  • Uterine Cervical Neoplasms* / pathology
  • rab GTP-Binding Proteins* / genetics
  • rab GTP-Binding Proteins* / metabolism
  • rab7 GTP-Binding Proteins
  • rhoC GTP-Binding Protein* / genetics
  • rhoC GTP-Binding Protein* / metabolism

Substances

  • rab GTP-Binding Proteins
  • rhoC GTP-Binding Protein
  • RHOC protein, human
  • rab7 GTP-binding proteins, human
  • rab7 GTP-Binding Proteins
  • GTPase-Activating Proteins