Role and regulation of autophagy-lysosomal proteolysis in cancer progression: insights from 2D and 3D models

Resveratrol counteracts IL-6-pro-growth effects, inducing a dormant state in ovarian cancer cells through autophagy. ARH-I (DIRAS3) is a target of miR-1305, an oncomiRNA upregulated by IL-6 and downregulated by RV. High expression of DIRAS3 and MAP1LC3B correlates with CDKN1A and predicts good prognosis, associated with MIR1305 downregulation. Maintaining dormancy in ovarian cancer through chronic RV could prevent the "awakening" of cancer cells. RV counteracts malignant activity induced by lysophosphatidic acid, a bioactive phospholipid abundant in the ovarian tumor microenvironment. LPA stimulates EMT, migration, spheroid growth, and chemo-resistance in ovarian cancer cells, while RV mitigates these effects. Bioinformatic analyses revealed the Hedgehog signaling pathway's involvement. LPA prevents autophagy, whereas RV restores it. Hh pathway dysregulation and impaired autophagy correlate with platinum resistance and poor prognosis. RV could be a therapy to impede metastasis and enhance chemosensitivity. Neuroblastoma is a childhood cancer causing significant fatalities. Cathepsin D, an aspartic protease in endosomal-lysosomal compartments, maintains protein homeostasis and influences cell growth. Dysfunctions in CD are linked to cancer. We explored CD's role in NB cell growth in suspension versus adherent conditions and its impact on metastatic behavior. CD inhibits EGF-induced NB cell proliferation in 2D by suppressing EGFR/MAPK signaling. Transgenic clones with silenced or overexpressed CD revealed that CD overexpression favored suspension growth, while suppression favored adherent growth. CD's dual role in 2D and 3D tumor growth suggests subclones with varying CD levels confer survival advantages during metastasis. We identified 38 miRNAs associated with cell adhesion and migration that reduce CD expression. CD expression could be epigenetically regulated during NB growth. Epigenetic targeting of CD could prevent NB metastases.