Inhibition of autophagy protein LC3A as a therapeutic target in ovarian clear cell carcinomas

Abstract

Objective: Ovarian clear cell carcinoma (CCC) is one of histological subtypes showing poor prognosis due to chemoresistance. The association of autophagy-related proteins and clinical implementation in CCC has not been determined.

Methods: The present study investigated whether expression of autophagy-related protein, light chain 3A (LC3A), was related with prognoses in the patients with CCC using immuno-histochemical stainings, and whether inhibition of autophagy modified the sensitivity to cisplatin in CCC cells in vitro.

Results: High expression of autophagy-related protein, LC3A, was detected in 78 cases (78%) in all CCC cases. The patients with high LC3A expression showed significantly lower response rate to primary chemotherapy (17% vs. 100%, p<0.010), and had worse progression-free survival (PFS) and overall survival (OS) compared with those with LC3A low expression. Furthermore, multivariate analyses revealed that high expression of LC3A was identified as independent worse prognostic factors for PFS and OS. Inhibition of autophagy protein LC3A using hydroxychloroquine (HCQ) increased sensitivity to cisplatin in CCC cells in vitro.

Conclusion: High expression of LC3A proteins was associated with lower response to platinum therapy, leading to worse prognoses in CCC. Although further studies are needed to confirm the results, inhibition of autophagy by HCQ was associated with platinum sensitivity. Autophagy protein LC3A could be a promising target for treatment for CCC.

Keywords: Adenocarcinoma, Clear Cell; Autophagy; Ovarian Neoplasms; Prognosis.