VNN1 overexpression in pancreatic cancer cells inhibits paraneoplastic islet function by increasing oxidative stress and inducing beta-cell dedifferentiation

Vanin-1 (VNN1) may be a potential biomarker for the early screening of pancreatic cancer (PC)-associated diabetes (PCAD). A previous study by the authors reported that cysteamine secreted by VNN1-overexpressing PC cells induced the dysfunction of paraneoplastic insulinoma cell lines by increasing oxidative stress. In the present study, it was observed that both cysteamine and exosomes (Exos) secreted by VNN1-overexpressing PC cells aggravated the dysfunction of mouse primary islets. PC-derived VNN1 could be transported into islets through PC cell-derived Exos (PC-Exos). However, beta-cell dedifferentiation, and not cysteamine-mediated oxidative stress, was responsible for the islet dysfunction induced by VNN1-containing Exos. VNN1 inhibited the phosphorylation of AMPK and GAPDH, and prevented Sirt1 activation and FoxO1 deacetylation in islets, which may be responsible for the induction of beta-cell de-differentiation induced by VNN1-overexpressing PC-Exos. Furthermore, it was demonstrated that VNN1-overexpressing PC cells further impaired the functions of paraneoplastic islets in vivo using diabetic mice with islets transplanted under the kidney capsule. On the whole, the present study demonstrates that PC cells overexpressing VNN1 exacerbate the dysfunction of paraneoplastic islets by inducing oxidative stress and beta-cell dedifferentiation.