Abstract
Recent studies have revealed that dysregulated Rab small GTPase-mediated vesicle trafficking pathways are associated with cancer progression. However, whether any of the Rabs plays a suppressor role in cancer stemness is least explored. Rab37 has been postulated as a tumor suppressive small GTPase for trafficking anti-tumor cargos. Here, we report a previously uncharacterized mechanism by which Rab37 mediates exocytosis of secreted frizzled-related protein-1 (SFRP1), an extracellular antagonist of Wnt, to suppress Wnt signaling and cancer stemness in vitro and in vivo. Reconstitution experiments indicate that SFRP1 secretion is crucial for Rab37-mediated cancer stemness suppression and treatment with SRPP1 recombinant protein reduces xenograft tumor initiation ability. Clinical results confirm that concordantly low Rab37, low SFRP1, and high Oct4 stemness protein expression profile can be used as a biomarker to predict poor prognosis in lung cancer patients. Our findings reveal that Rab37-mediated SFRP1 secretion suppresses cancer stemness, and dysregulated Rab37-SFRP1 pathway confers cancer stemness via the activation of Wnt signaling. Rab37-SFRP1-Wnt axis could be a potential therapeutic target for attenuating lung cancer stemness.
Highlights
Introduction Rab smallGTPases regulate vesicular transport between different organelles in distinct intracellular compartment through changing its guanine nucleotide binding status between GTP-bound form and GDP-bound form[1,2,3]
We further investigated the ability of tumor initiation in mice xenograft models
The results showed that Rab37 wild-type (Rab37WT) or Rab37Q89L overexpression group had reduced sphere size and number compared to the empty vector control (EV) or Rab37T43N group (Figs. 1g, h)
Summary
Introduction Rab smallGTPases regulate vesicular transport between different organelles in distinct intracellular compartment through changing its guanine nucleotide binding status between GTP-bound form (active state) and GDP-bound form (inactive state)[1,2,3]. Rab2A, Rab3D, Rab[8], Rab[11], Rab[21], Rab22A, Rab[23], Rab[25], Rab27B, and Rab[35] promote tumor cell migration, invasion and metastasis by disrupting the homeostasis of intracellular signal. We previously identified Rab[37] which shows tumor suppressor function by regulating exocytosis of thrombospondin-1 and tissue inhibitor of metalloproteinase 1 to the extracellular compartment, leading to inhibition of Official journal of the Cell Death Differentiation Association. We report a novel anticancer stemness function of Rab[37], which mediates secreted frizzled-related protein-1 (SFRP1), an extracellular antagonist of Wnt[19,20,21], for exocytosis to suppress cancer stemness. Targeting Rab37-SFRP1-Wnt signaling may have therapeutic value in treating lung cancer
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