Knockdown of WAVE1 enhances apoptosis of leukemia cells by downregulating autophagy

Zhang,Zhaoxia; Wu,Benqing; Chai,Wenwen; Cao,Lizhi; Wang,Yangping; Yu,Yan; Yang,Liangchun

doi:10.3892/ijo.2016.3446

Knockdown of WAVE1 enhances apoptosis of leukemia cells by downregulating autophagy

Authors:
- Zhaoxia Zhang
- Benqing Wu
- Wenwen Chai
- Lizhi Cao
- Yangping Wang
- Yan Yu
- Liangchun Yang
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Affiliations: Department of Pediatrics, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China, Department of Nuclear Medicine, Hu Nan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China, Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: March 18, 2016 https://doi.org/10.3892/ijo.2016.3446
Pages: 2647-2656

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Abstract

Chemoresistance of leukemia constitutes a great challenge for successful treatment of leukemia. Autophagy has recently attracted increasing attention for its role in conferring resistance to various conventional anti-neoplastic regiments. In the present study, the authors showed that WAVE1, a member of WASP family verprolin-homologous proteins, is a critical regulator of chemoresistance during autophagy. It is positively correlated with clinical status in pediatric acute myeloblastic leukemia (AML) and leukemia cell lines. The knockdown of WAVE1 expression decreased autophagy was accompanied by an upregulation of autophagic marker microtubule-associated protein light chain 3 (LC3)-Ⅱ, a degradation of SQSTM1/sequestosome 1 (p62) and the formation of autophagosomes. Moreover, a suppression of WAVE1 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis, and depletion of WAVE1 expression promoted the translocation of Bcl-2 from mitochondria into the cytoplasm. In addition, a knockdown of PI3K-Ⅲ expression significantly inhibited WAVE1-mediated autophagy. Furthermore, suppression of WAVE1 expression blocked the interactions between Beclin1 and PI3K-Ⅲ and the disassociation of Beclin1-Bcl-2 during enhanced autophagy. The above results suggested that WAVE1 is a critical pro-autophagic protein capable of enhancing cell survival and regulating chemoresistance in leukemia cells potentially through the Beclin1/Bcl-2 and Beclin1/PI3K-Ⅲ complex-dependent pathways.

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