New Insights Into Beclin-1: Evolution and Pan-Malignancy Inhibitor Activity

Stephen L Wechman; Anjan K Pradhan; Rob DeSalle; Swadesh K Das; Luni Emdad; Devanand Sarkar; Paul B Fisher

doi:10.1016/bs.acr.2017.11.002

New Insights Into Beclin-1: Evolution and Pan-Malignancy Inhibitor Activity

Adv Cancer Res. 2018:137:77-114. doi: 10.1016/bs.acr.2017.11.002. Epub 2017 Dec 27.

Authors

Stephen L Wechman¹, Anjan K Pradhan¹, Rob DeSalle², Swadesh K Das³, Luni Emdad³, Devanand Sarkar³, Paul B Fisher⁴

Affiliations

¹ Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
² Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY, United States.
³ Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
⁴ Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States. Electronic address: paul.fisher@vcuhealth.org.

Abstract

Autophagy is a functionally conserved self-degradation process that facilitates the survival of eukaryotic life via the management of cellular bioenergetics and maintenance of the fidelity of genomic DNA. The first known autophagy inducer was Beclin-1. Beclin-1 is expressed in multicellular eukaryotes ranging throughout plants to animals, comprising a nonmonophyllic group, as shown in this report via aggressive BLAST searches. In humans, Beclin-1 is a haploinsuffient tumor suppressor as biallelic deletions have not been observed in patient tumors clinically. Therefore, Beclin-1 fails the Knudson hypothesis, implicating expression of at least one Beclin-1 allele is essential for cancer cell survival. However, Beclin-1 is frequently monoallelically deleted in advanced human cancers and the expression of two Beclin-1 allelles is associated with greater anticancer effects. Overall, experimental evidence suggests that Beclin-1 inhibits tumor formation, angiogenesis, and metastasis alone and in cooperation with the tumor suppressive molecules UVRAG, Bif-1, Ambra1, and MDA-7/IL-24 via diverse mechanisms of action. Conversely, Beclin-1 is upregulated in cancer stem cells (CSCs), portending a role in cancer recurrence, and highlighting this molecule as an intriguing molecular target for the treatment of CSCs. Many aspects of Beclin-1's biological effects remain to be studied. The consequences of these BLAST searches on the molecular evolution of Beclin-1, and the eukaryotic branches of the tree of life, are discussed here in greater detail with future inquiry focused upon protist taxa. Also in this review, the effects of Beclin-1 on tumor suppression and cancer malignancy are discussed. Beclin-1 holds significant promise for the development of novel targeted cancer therapeutics and is anticipated to lead to a many advances in our understanding of eukaryotic evolution, multicellularity, and even the treatment of CSCs in the coming decades.

Keywords: Autophagy; BLAST; Beclin-1; Cancer stem cells; Cancer therapy; Molecular evolution; Oncogenesis; Tumor suppressor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antineoplastic Agents / therapeutic use*
Beclin-1 / metabolism*
Evolution, Molecular*
Genes, Tumor Suppressor
Humans
Molecular Targeted Therapy*
Neoplasms / drug therapy*
Neoplasms / metabolism*
Neoplasms / pathology

Substances

Antineoplastic Agents
Beclin-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding