Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

Elgendy, Mohamed; Cirò, Marco; Abdel-Aziz, Amal Kamal; Belmonte, Giuseppe; Zuffo, Roberto Dal; Mercurio, Ciro; Miracco, Clelia; Lanfrancone, Luisa; Foiani, Marco; Minucci, Saverio

doi:10.1038/ncomms6637

Cited by 71 publications

(72 citation statements)

References 38 publications

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“…50 Along a similar vein, Beclin-1 and the antiapoptotic Bcl-2 family member myeloid cell leukemia (Mcl-1) protein are both stabilized by binding to the deubiquitinase USP9X (ubiquitin-specific peptidase 9 X-linked), and negatively modulate the expression of each other through competitive displacement of USP9X. 51 Beclin-1 expression levels were discovered to decrease in patient-derived melanoma tissues as Mcl-1 levels increased in a significant interdependent manner, independent of autophagy. 51 Though Beclin-1 has recently been demonstrated to have a role in the response of lung cancer to epidermal growth factor receptor inhibition, 52 further experimental validation is needed to determine the practical consequences of BECN1 heterozygosity in human tumors and to delineate whether the observations involving Beclin-1 are indeed dependent on the role autophagy serves in each of these experimental systems, or rather due to the confounding implications BRCA1, p53 and Mcl-1 each provide on cancer cell viability and disease progression.…”

Section: Mouse Models Address the Role Of Autophagy In Tumor Initiatimentioning

confidence: 99%

Emerging strategies to effectively target autophagy in cancer

2015

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Autophagy serves a dichotomous role in cancer and recent advances have helped delineate the appropriate settings where inhibiting or promoting autophagy may confer therapeutic efficacy in patients. Our evolving understanding of the molecular machinery responsible for the tightly controlled regulation of this homeostatic mechanism has begun to bear fruit in the way of autophagy-oriented clinical trials and promising lead compounds to modulate autophagy for therapeutic benefit. In this manuscript we review the recent preclinical and clinical therapeutic strategies that involve autophagy modulation in cancer.

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Section: Mouse Models Address the Role Of Autophagy In Tumor Initiatimentioning

confidence: 99%

Emerging strategies to effectively target autophagy in cancer

2015

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“…However, since autophagy is executed independently of ATG7, perhaps it is dispensable contextually, and evaluation of autophagy proteins like tumor suppressor Beclin-1 might provide a more complete picture of the significance of autophagy during melanocyte transformation. Mechanistically, Beclin-1 is a negative regulator of Myeloid Cell Leukemia 1 (Mcl-1) and promotes proteasomal degradation of Mcl-1 to restrain melanocyte transformation [58]. The autophagic protein, Beclin-1 constitutively suppressed melanocyte transformation, and loss of the protein in patients contributed to increased Mcl-1 and melanoma progression [58].…”

Section: Role Of Autophagymentioning

confidence: 99%

Autophagy: In the cROSshairs of cancer

Hambright

Ghosh

2017

Biochemical Pharmacology

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Two prominent features of tumors that contribute to oncogenic survival signaling are redox disruption, or oxidative stress phenotype, and high autophagy signaling, making both phenomena ideal therapeutic targets. However, the relationship between redox disruption and autophagy signaling is not well characterized and the clinical impact of reactive oxygen species (ROS)-generating chemotherapeutics on autophagy merits immediate attention as autophagy largely contributes to chemotherapeutic resistance. In this commentary we focus on melanoma, using it as an example to provide clarity to current literature regarding the roles of autophagy and redox signaling which can be applicable to initiation and maintenance of most tumor types. Further, we address the crosstalk between ROS and autophagy signaling during pharmacological intervention and cell fate decisions. We attempt to elucidate the role of autophagy in regulating cell fate following treatment with ROS-generating agents in preclinical and clinical settings and discuss the emerging role of autophagy in cell fate decisions and as a cell death mechanism. We also address technical aspects of redox and autophagy evaluation in experimental design and data interpretation. Lastly, we present a provocative view of the clinical relevance, emerging challenges in dual targeting of redox and autophagy pathways for therapy, and the future directions to be addressed in order to advance both basic and translational aspects of this field.

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“…mTOR is a master regulator of autophagy, and MCL-1 has also been shown to inhibit autophagy through negative regulation of autophagy essential mediator beclin 1 (22,36,37). A few recent studies investigated the interplay between sunitinib and autophagy and led to different conclusions (49)(50)(51)(52).…”

Section: Sunitinib Exerts Dual Effects On Mcl-1 and Mtor In Tolerant Andmentioning

confidence: 99%

“…Tight MCL-1 regulation coupled with its short half-life hints that its activities may be finely tuned in response to different cellular stresses. MCL-1 is among the most highly upregulated oncoproteins in several types of tumors and has been shown to directly contribute to chemoresistance of those tumors (19)(20)(21)(22). Targeting MCL-1 is therefore emerging as a promising therapeutic strategy, with several inhibitors under development (19,(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%