Abstract Autophagy plays a dual role in cancer, promoting tumour growth by recycling cellular substrates while also triggering autophagy-dependent cell death (ADCD) under excessive activation. The STRIPAK (striatin-interacting phosphatase and kinase) complex, known for its role in cancer progression, has recently been identified as a regulator of autophagy markers. Pancreatic cancer, one of the most aggressive malignancies, is characterised by late diagnosis, and poor survival. Despite elevated autophagy levels, clinical trials with autophagy inhibitors have shown limited survival benefits. This study investigates the clinical significance of key autophagy markers in pancreatic cancer patients, with a focus on the regulatory role of STRN3, a core member of the STRIPAK complex, in autophagy regulation. Through the analysis of a pancreatic adenocarcinoma cDNA cohort (n=223), we identified STRN3 and SQSTM1 as significant poor prognostic indicators. Integrated expression profiling of STRN3, SQSTM1, and BECN1 highlights their potential as a prognosis biomarker signature. STRN3 knockdown and overexpression models were generated using pancreatic cancer cell lines. Knockdown of STRN3 led to increased BECN1 and reduced SQSTM1 protein expression. Protein interaction of STRN3 with SQSTM1 and LC3 were further identified via co-immunoprecipitation. Using the mRFP-EGFP-LC3 plasmid, we observed increased autophagic flux in the STRN3 knockdown cell models, whereas overexpression of STRN3 significantly reduced autophagosome formation. STRN3 is a critical regulator of autophagy, influencing both autophagosome formation and degradation. These findings provide novel insights into STRN3's role in pancreatic cancer biology and highlight its potential as a therapeutic target. Further studies are warranted to elucidate the underlying molecular mechanisms.
Li et al. (Fri,) studied this question.
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