Imatinib induces autophagy through<i>BECLIN‐1</i>and<i>ATG5</i>genes in chronic myeloid leukemia cells

Can, Geylani; Ekiz, H. Atakan; Baran, Yusuf

doi:10.1179/102453311x12902908412039

Cited by 35 publications

(20 citation statements)

References 33 publications

(32 reference statements)

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“…21,22 This survival pathway will limit imatinib-induced cell death and promote the formation of imatinib resistance. 2,3,23 In this study, we identified dysregulated miR-30a as an important event that mediated autophagy during imatinib treatment. Imatinib inhibits miR-30a, but not miR-101 and miR-32, expression in CML cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

et al. 2012

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A major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib and other BCR-ABL tyrosine kinase inhibitors. MicroRNAs (miRNAs) are small RNA molecules that influence gene expression by post-transcriptional regulation of messenger RNA. It is not yet clear how miRNAs are able to regulate the effectiveness of imatinib in CML. Here, we show that imatinib markedly inhibits expression of miR-30a in human CML cells. miR-30a is a potent inhibitor of autophagy by downregulating Beclin 1 and ATG5 expression. miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomir-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity. These findings indicate that dysregulation of miR-30a may interfere with the effectiveness of imatinib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target in CML.

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Section: Discussionmentioning

confidence: 99%

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

et al. 2012

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“…38,56 In addition, both ATG5 and BECLIN-1 were found to be For personal use only. on May 11, 2018. by guest www.bloodjournal.org From For personal use only.…”

Section: Discussionmentioning

confidence: 99%

The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells

Rothe

Lin

et al. 2014

Blood

161

152

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Key Points• The core autophagy protein ATG4B is highly expressed in CML stem/progenitor cells and may be useful in predicting treatment response.• ATG4B knockdown reduces autophagy, impairs the survival of CML stem/progenitor cells, and sensitizes them to IM treatment.Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34 1 hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34 1 cells from chronicphase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34 1 CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naïve CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells. (Blood. 2014;123(23):3622-3634)

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“…66,67) Furthermore, it is reported that imatinib induces autophagy in chronic myeloid leukemia cells by inducing the overexpression of Beclin-1. 68) However, in the Western blot analysis of harmol-treated A549 cells, changes in the protein expression and phosphorylation levels of Bcl-2 and Beclin-1 were not observed (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

Abe

Yamada

Moriya

et al. 2011

Biological & Pharmaceutical Bulletin

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Lung cancer is a leading cause of death worldwide, and the long-term survival rate of lung cancer patients is one of the lowest among cancers.1,2) Two major types of lung cancer have been identified: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC, the most prevalent subtype, is relatively resistant to chemotherapy and radiation therapy. On the other hand, SCLC is initially highly sensitive to chemotherapy and radiation therapy, but shows resistance to treatment in the majority of patients.3) The high mortality in NSCLC is due to the difficulty of early diagnosis and its high potential for local invasion and distant metastasis. Although relatively effective chemotherapeutic agents have been developed, lung cancer still has a low cure rate. Furthermore, the adverse effects of chemotherapeutic compounds often hamper the quality of life of lung cancer patients. Therefore, the discovery of effective novel prophylactic, diagnostic, and therapeutic treatments for NSCLC is urgently needed."Apoptosis" has been used as a synonym for programmed cell death (PCD), and is a well-known form of PCD. Since the 1960s, various morphological forms of PCD have been recognized. Clarke classified cell death into 4 types, including type I PCD (apoptosis) and type II PCD (autophagy). 4)Numerous studies have demonstrated that most chemotherapy agents and certain naturally occurring compounds induce cell death by activating the apoptotic pathway. It is thought that apoptosis induction in tumor cells with either drugs or natural products is effective therapy for cancer and immune system diseases. On the other hand, autophagy is one of the major regulatory mechanisms in the degradation of intracellular proteins and organelles. 5,6) During autophagy, the cytosol and whole organelles become encased in double-membrane vacuoles such as autophagosomes, and subsequently fuse with lysosomes.5) Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.7) Although originally characterized as a survival response to nutrient deficiency, autophagy is now recognized as frequently induced in response to a variety of stressors to maintain cellular homeostasis. [8][9][10][11][12] In recent years, the importance of autophagy has been emphasized in various biological fields, including cancer. 9,[13][14][15] Furthermore, cancer cells show less autophagy than normal cells. 16,17) These findings indicate that autophagy induction is an attractive modality of anticancer therapy.b-Carboline alkaloids occur in a number of medicinal plants such as Peganum harmala, Passiflora edulis, Passiflora incarnata, and Banisteriopsis caapi.18,19) These plants have been used in traditional medicine to treat asthma, jaundice, lumbago, and other human ailments.19-21) Recently, it has been reported that certain b-carboline alkaloids and their related compounds have cytotoxic effects on cancer cells. [22][23][24] We also reported previously that harm...

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Imatinib induces autophagy throughBECLIN‐1andATG5genes in chronic myeloid leukemia cells

Cited by 35 publications

References 33 publications

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

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