Wheat germ agglutinin-induced paraptosis-like cell death and protective autophagy is mediated by autophagy-linked FYVE inhibition

// Tsung Lin Tsai 1, 3 , Hao Chen Wang 2 , Chun Hua Hung 1 , Peng Chan Lin 1 , Yi San Lee 1 , Helen H.W. Chen 3 and Wu Chou Su 1 , 2 1 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Insititue of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3 Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Correspondence to: Wu Chou Su, email: sunnysu@mail.ncku.edu.tw Helen H.W. Chen, email: helen@mail.ncku.edu.tw Keywords: cell death, wheat germ agglutinin, paraptosis, cytoplasmic vacuolation, Alfy Received: February 03, 2017     Accepted: July 11, 2017     Published: August 24, 2017 ABSTRACT Wheat germ agglutinin (WGA) is a lectin that specifically binds cell surface glycoproteins and disrupts nuclear pore complex function through its interaction with POM121. Our data indicate WGA induces paraptosis-like cell death without caspase activation. We observed the main features of paraptosis, including cytoplasmic vacuolation, endoplasmic reticulum dilation and increased ER stress, and the unfolded protein response in WGA-treated cervical carcinoma cells. Conversion of microtubule-associated protein I light chain 3 (LC3-I) into LC3-II and punctuate formation suggestive of autophagy were observed in WGA-treated cells. WGA-induced autophagy antagonized paraptosis in HeLa and CaSKi cells, which expressed autophagy-linked FYVE (Alfy) protein, but not in SiHa cells that did not express Alfy. Alfy knockdown in HeLa cells induced paraptosis-like cell death. These data indicate that WGA-induced cell death occurs through paraptosis and that autophagy may exert a protective effect. WGA treatment and Alfy inhibition could be an effective therapeutic strategy for apoptosis-resistant cervical cancer cells.