Downregulation of uPAR and Cathepsin B Induces Apoptosis via Regulation of Bcl-2 and Bax and Inhibition of the PI3K/Akt Pathway in Gliomas

Malla, Rama Rao; Gopinath, Sreelatha; Alapati, Kiranmai; Gondi, Christopher S.; Gujrati, Meena; Dinh, Dzung H.; Mohanam, Sanjeeva; Rao, Jasti S.

doi:10.1371/journal.pone.0013731

Cited by 86 publications

(64 citation statements)

References 59 publications

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“…51 A notable target among these proteases is cathepsin B, a protease implicated in apoptosis via its cleavage-activating capacity aimed at Bcl-2 family members, resulting in disruption of the mitochondrial membrane and cytochrome c release. 52 Before our study no equivalent downstream substrate for cathepsin B in the autophagy process had been identified. However, the Bcl-2 protein family is known to facilitate crosstalk between apoptosis and autophagy, 53,54 raising the possibility for a role for cathepsins in cellular autophagy.…”

Section: Discussionmentioning

confidence: 98%

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Goussetis

Gounaris

et al. 2012

Blood

117

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We provide evidence that arsenic trioxide (As 2 O 3 ) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or ca- IntroductionElements of the autophagic machinery have attracted recently considerable attention as a potential target for the development of novel approaches for the treatment of malignancies. 1,2 Similar to apoptosis, autophagy is a programmed cell death mechanism, but it is distinguished by a self-catabolic process involving lysosomal proteolytic degradation of cellular components. 3 This is initiated by the formation of a double-membrane enclosed structure, known as the autophagosome. 4 On fusion with a lysosome, a cellular organelle characterized by low pH and hydrolytic enzymes, 5,6 such structure eventually develops into the autophagolysosome where degradation of organelles occurs.Under different circumstances, autophagy can either inhibit or promote malignant cell survival, but its precise role in tumorigenesis remains to be established. 7,8 The role of inducible autophagy in BCR-ABL expressing leukemia cells is poorly understood. For example, there is previous evidence suggesting that autophagy may play regulatory roles in BCR-ABL leukemogenesis, 9 whereas other studies have shown that pharmacologic inhibition of autophagy enhances the effects of imatinib mesylate and other targeted therapies in CML. [10][11][12] There are also opposing lines of evidence, pointing toward tumor inhibitory effects of autophagy, 13,14 although a recent study demonstrated that BCR-ABL exerts suppressive effects on autophagy via engagement of the PI3K/FoxO4/ATF5/ mTOR pathway. 15 Arsenic trioxide (AS 2 O 3 ) exhibits potent antileukemic effects in vitro and in vivo and has major clinical activity in the treatment of patients with acute promyelocytic leukemia (APL). [16][17][18] This agent was previously shown to target and eliminate leukemia initiating stem cells (LICs) in mouse models in vivo via PML targeting. 19 Notably, there is evidence that AS 2 O 3 degrades BCR-ABL, 20 raising the possibility that this agent may provide an approach to target CML LICs. However, a major limiting factor for the incorporation of arsenic in non-APL malignancies has been the requirement of high concentrations for induction of cell death in non-APL cells and the incomplete understanding of the mechanisms by which it promotes antileukemic responses.A major mechanism contributing to the antineoplastic effects of arsenic is induction of apoptosis, 16-18 with upstream JNK activation being a prominent regulatory mechanism. 21 In a recent study, we provided evidence that arsenic trioxide induces autophagy in AML leukemic progenitors and demonstrated that such autophagy is essential for generation of the inhibitory effects of arsenic on primitive leukemic precursors. 22 However, the key downstream cellular events by which such arsenic-de...

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Section: Discussionmentioning

confidence: 98%

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Goussetis

Gounaris

et al. 2012

Blood

117

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“…It has been observed that uPAR affects cell proliferation, differentiation, migration and invasion in glioma, papillary thyroid carcinoma, lung cancer, prostate cancer and other malignancies; all of these functions may be associated with the activation of signaling pathway intracelluar, such as Akt and ERK, as well as angiogenesis within the tumor. 23 In addition, TLR2-mediated synthesis and release of TNF-α and IL-6 by neutrophils was closely related to uPAR. 24 RA-FLSs, as a particular population in synovium, have tumor cell characteristics under chronic inflammatory stimulation, and in which, TNF-α and IL-6 are crucial inflammatory cytokines.…”

Section: Upar Knockdown Decreases Ra-flss Migration and Invasion In Vmentioning

confidence: 98%

uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis

et al. 2017

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“…Failure to trigger the cellular suicide program not only predisposes to development of malignancies, but also increases the resistance of gliomas to anticancer drugs and irradiation (33). Apoptosis is a tightly regulated form of programmed cell death involving a series of biochemical events (34)(35)(36), in which Bcl-2 gene has been proved to play a critical role in the key events of mitochondrial apoptosis (37)(38)(39). The Bcl-2 belongs to a superfamily of genes known to be involved in the regulation of the cell death process, and is predominantly localized in mitochondria that regulates mitochondrial membrane integrity and cytochrome c release (40,41).…”

Section: Discussionmentioning

confidence: 99%

Expression and correlation of Bcl-2 with pathological grades in human glioma stem cells

2012

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Abstract. The anti-apoptotic gene, B-cell lymphoma-2 (Bcl-2), has been reported to be overexpressed in gliomas and is related to tumor prognosis, suggesting a potential therapeutic target. Additionally, recent studies have demonstrated the existence of brain glioma stem cells (BGSCs) which are tumorigenic, selfrenewable and dominate the biological behavior of gliomas. Currently BGSCs are committed as a new target of glioma therapies. However, few studies have focused on the expression of Bcl-2 in BGSCs. We performed a series of experiments to culture BGSCs from eight clinical specimens, followed by real-time RT-PCR and immunoassays to compare the expression levels of Bcl-2 in BGSCs and their corresponding primary glioma cells (PGCs). The results showed that Bcl-2 mRNA and protein expression levels are higher in BGSCs compared to their counterparts, and the expression levels are related to glioma malignancies. As an anti

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Downregulation of uPAR and Cathepsin B Induces Apoptosis via Regulation of Bcl-2 and Bax and Inhibition of the PI3K/Akt Pathway in Gliomas

Cited by 86 publications

References 59 publications

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis

Expression and correlation of Bcl-2 with pathological grades in human glioma stem cells

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