Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Abstract

Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.

Knockdown of CFTR enhances sensitivity of prostate cancer cells to cisplatin via inhibition of autophagy

“…Several previous studies have shown that autophagy can trigger autophagic death pathway, which is the predominant cell death mechanism in response certain chemotherapy [27,28]. On the other hand, many studies have proved that autophagy can also protect cells from apoptosis and various stress to counteract cell death after chemotherapy [6,7,11,29]. Therefore, autophagy is considered as an important target in intervention and treatment of cancers [30], and autophagymodulating agents also have been identified as potential cancer therapeutic agents [31].…”

“…suggested to serve as a pro-survival mechanism that facilitates cancer cells to resistance therapy-induced cell death [7]. To verify this consumption, we firstly analyzed cell viability in LNCaP cells or LNCaP/CP cells in the presence or absence of 3MA.…”

“…Although previous studies have suggested various mechanisms of chemoresistance, autophagy plays a critical role in the develop-ment of chemoresistance [5][6][7]. Autophagy is an evolutionarily conserved catabolic process that could degrade unnecessary or dysfunctional cytoplasmic components via endosomes and lysosomes to maintain the cellular energy supply and homeostasis [8,9].…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…205,209 However, in leukemia patients, high doses of CQ are needed to inhibit autophagy, which limits their therapeutic efficacy. 205,209 However, in leukemia patients, high doses of CQ are needed to inhibit autophagy, which limits their therapeutic efficacy.…”

“…Chloroquine and other inhibitors of autophagy have cytotoxic effects on diverse leukemia-initiating cell types such as CD34-positive and glucocorticoid-resistant clones. 205,209 However, in leukemia patients, high doses of CQ are needed to inhibit autophagy, which limits their therapeutic efficacy. 210 One potential explanation comes from the observation that CQ may kill leukemia cells independently from the early steps of the autophagy pathway, and this CQ effect can be neutralized by leukemia cells in vivo through exocytosis.…”