Knockdown of WAVE1 enhances apoptosis of leukemia cells by downregulating autophagy

Abstract

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.

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

“…This may reflect WASp-independent polymerisation of actin via the ARP2/3 complex, which may be of particular importance in potential for compensatory mechanisms to restore some autophagic activity essential for cell survival in WASp deficiency. Our findings here are supported by extensive work by others in non-haematopoietic cell line models that highlight the importance of actin at various stages of the autophagy process [reviewed in (Kast and Dominguez, 2017), (Coutts and La Thangue, 2016) and (Kruppa et al, 2016)], for which ARP2/3 and WASp family members have been particularly implicated (Kast et al, 2015, Coutts and La Thangue, 2015, Xia et al, 2013, Xia et al, 2014, King et al, 2013, Zavodszky et al, 2014, Zhang et al, 2016.…”

The actin nucleation factors JMY and WHAMM enable a rapid p53-dependent pathway of apoptosis

“…has been one of the most studied members, as it can influence the localization or modification of Bcl-2-family proteins. Transient overexpression and depletion experiments suggest that WAVE1 limits mitochondrial permeabilization in a cell type dependent manner [20][21][22][23]. But in our study, permanently knocking out the gene encoding WAVE1 in BCR-ABL-immortalized human cells increased the frequency of apoptosis in only 1 of 3 experiments.…”

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Heterogeneous nuclear ribonucleoprotein K (hnRNP K) may be associated with the development of ADM resistance in AML by augmenting autophagy (34). Inhibition of WAVE1 expression enhances the sensitivity of leukemia cells to chemotherapy by downregulating autophagy (35). All this research indicates that autophagy is a mechanism involved in chemotherapy resistance of various leukemia cells.…”