Abstract
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy.
Highlights
Chronic myelogenous leukemia (CML) is a myeloproliferative syndrome linked to a hematopoietic stem cell disorder leading to the increased production of granulocytes at all stages of differentiation [1]
We previously reported that treatment of imatinib-sensitive (IM-S) or IM-R K562 cells with RSV for 24 to 48 hours resulted in loss of cell viability and induction of apoptosis [13]
Coimmunoprecipitation analysis established that endogenous LC3 and p62 interacted together (Fig. 1C). Both LC3-I and LC3-II were able to interact with p62 in IM-S and IM-R cells and this interaction was increased in RSVtreated cells
Summary
Chronic myelogenous leukemia (CML) is a myeloproliferative syndrome linked to a hematopoietic stem cell disorder leading to the increased production of granulocytes at all stages of differentiation [1]. RSV has been reported to either protect CML cell lines from stress-induced apoptosis mainly through its antioxidant properties [10], or to induce cell death when used alone [11]. The molecular mechanisms by which RSV exerts its antileukemic effects in CML cell lines remains incompletely understood [12]. We have previously reported that RSV induces apoptosis in CML cell lines. We have shown that RSV triggered cell death in imatinib-resistant (IM-R) cell lines and in Baf/3 cells carrying several mutated forms of BCRABL commonly found in resistant patients [13]. The effects of RSV in CML cells are only partly inhibited by caspase inhibitors, strongly suggesting that RSV exerts its potent antileukemic effect through caspase-independent cell death
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