CYB5A Induces Autophagy, and Higher Expression Improves Survival in Pancreatic Cancer

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Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma. In a study reported in the Journal of the National Cancer Institute, Giovannetti and colleagues assessed the role of 18q22.3-encoded CYB5A in pancreatic cancer prognosis and autophagy modulation.

In the study, both resected (n = 130) and metastatic (n = 50) patients with low CYB5A mRNA or protein expression had significantly shorter overall survival compared with patients with higher expression levels (eg, median 16.7 vs 24.8 months, P = .02, among patients with radical resection). Studies in pancreatic ductal adenocarcinoma cell lines showed that increased CYB5A expression was associated with autophagy induction and reduced proliferation and migration/invasion of cancer cells.

Network analysis of pro-autophagic signaling pathways indicated an interaction of CYB5A with TRAF6, an interaction that was confirmed by observation of downregulation of TRAF6 after CYB5A reconstitution (–69% in SU.86.86-CYB5A-positive cell lines, P = .005). CYB5A silencing restored TRAF6 expression and wound healing. Studies in CYB5A-positive orthotopic mouse models showed that CYB5A-induced autophagy, inhibited pancreatic tumor growth/metastasis, and increased survival (median, 57 vs 44 days, P = .03).

The investigators concluded, “These results define CYB5A as a novel prognostic factor for [pancreatic ductal adenocarcinoma] that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.”

Giovannetti E, et al: J Natl Cancer Inst 106(1):djt346, 2014.