Essential roles of Caspase-3 in facilitating Myc-induced genetic instability and carcinogenesis

Abstract

The mechanism for Myc-induced genetic instability is not well understood. Here we show that sublethal activation of Caspase-3 plays an essential, facilitative role in Myc-induced genomic instability and oncogenic transformation. Overexpression of Myc resulted in increased numbers of chromosome aberrations and γH2AX foci in non-transformed MCF10A human mammary epithelial cells. However, such increases were almost completely eliminated in isogenic cells with CASP3 gene ablation. Furthermore, we show that endonuclease G, an apoptotic nuclease downstream of Caspase-3, is directly responsible for Myc-induced genetic instability. Genetic ablation of either CASP3 or ENDOG prevented Myc-induced oncogenic transformation of MCF10A cells. Taken together, we believe that Caspase-3 plays a critical, unexpected role in mediating Myc-induced genetic instability and transformation in mammalian cells.DOI: http://dx.doi.org/10.7554/eLife.26371.001

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

“…Although MOMP and caspase-3 activation continue to be used as molecular markers of cell death, relatively recent studies demonstrated that, under some circumstances, instead of functioning as an apoptosis executioner, active caspase-3 plays an important role in carcinogenesis, metastasis, and therapy resistance (reviewed in [107,[112][113][114][115][116][117][118][119][120]). Caspase-3 can stimulate tumor cell growth through various routes.…”

Cellular plasticity, caspases and autophagy; that which does not kill us, well, makes us different

“…In the second bucket, caspases cleave proteins to affect cell behaviour in the same cell (reviewed in [ 41 ]). Examples include sperm tail individualization in Drosophila [ 48 , 49 ], cleavage and activation of Wg-inhibitor Sgg to temper Wg signalling during Drosophila neurogenesis [ 50 ], cleavage and activation of endonuclease G to result in genome instability and oncogenic transformation in human cells [ 51 , 52 ], and cleavage of NANOG to allow mouse ESCs to differentiate [ 53 ]. In the last study, mouse NANOG was cleaved by caspase 9 in vitro , cleavage products were detected in differentiating ESCs, and the expression of a caspase-resistant NANOG prevented ESCs from differentiating.…”

Q&A: Cellular near death experiences—what is anastasis?

“…In 2015, Liu et al reported that MCF10A cells can survive with activated caspase 3 after exposure to low-dose 56 Fe ion irradiation (<3 Gys) [ 17 ]. Recently, the same group reported some MCF10A cells can escape cell death induced by Myc overexpression even though caspase 3 was activated [ 18 ]. Ichim et al found ABT-737, a prototypic BH3-mimetic compound, induced mitochondrial outer membrane permeabilization (MOMP) in a small fraction of mitochondria, leading to sublethal caspase 3 activation [ 19 ].…”