Novel roles of apoptotic caspases in tumor repopulation, epigenetic reprogramming, carcinogenesis, and beyond

Abstract

Apoptotic caspases have long been studied for their roles in programmed cell death and tumor suppression. With recent discoveries, however, it is becoming apparent these cell death executioners are involved in additional biological pathways beyond killing cells. In some cases, apoptotic cells secrete growth signals to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues in multiple organisms, but it also poses problems in tumor resistance to chemo- and radiotherapy. Additionally, it was found that activation of caspases does not irreversibly lead to cell death, contrary to the established paradigm. Sub-lethal activation of caspases is evident in cell differentiation and epigenetic reprogramming. Furthermore, evidence indicates spontaneous, unprovoked activation of caspases in many cancer cells, which plays pivotal roles in maintaining their tumorigenicity and metastasis. These unexpected findings challenge current cancer therapy approaches aimed at activation of the apoptotic pathway. At the same time, the newly discovered functions of caspases suggest new treatment approaches for cancer and other pathological conditions in the future.

Low expression of pro-apoptotic proteins Bax, Bak and Smac indicates prolonged progression-free survival in chemotherapy-treated metastatic melanoma

“…For example, it was suggested that expression patterns indicative of high apoptosis responsiveness may correlate with poor outcome if dormant, stem-like cancer cells that may reside within tumour tissues re-populate tumours and promote further spread and progression of the disease after the bulk population of cells has been eliminated by apoptosisinducing therapy 42,43 . In line with this, apoptotic cell loss can drive the proliferation of surrounding cells, for example, through caspase-dependent prostaglandin signalling and secretion of other proliferation stimulating factors from dying cells 60,61 . These signalling processes indeed might be of relevance in melanoma treatment responsiveness and disease relapse 62 .…”

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

“…Genotoxic anticancer agents activate the mitochondrial or intrinsic pathway of apoptosis (reviewed in [106][107][108]). The process is initiated by mitochondrial outer membrane permeabilization (MOMP), resulting in the release of cytochrome c and other intermembrane space proteins.…”

“…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.…”

“…One route involves caspase-3-mediated secretion of pro-survival factors such as prostaglandin E 2 that promote enrichment of tumor repopulating cells [115][116][117][118][119]. Another route is through caspase-3/DNase-mediated accumulation of genome instability (e.g., DNA double-strand breaks) that trigger ATM-dependent activation of the transcription factors NF-κB and STAT3, known drivers of tumor growth [107,120]. In addition to secreting pro-survival factors, apoptotic cells release exosomes (nano-sized lipid vesicles containing proteins, nucleic acids, micro RNAs, etc.)…”

“…In addition to secreting pro-survival factors, apoptotic cells release exosomes (nano-sized lipid vesicles containing proteins, nucleic acids, micro RNAs, etc.) that maintain the viability of the neighboring cells [107,114,121]. Caspase 3 appears to play a role in a late phase of exosome biosynthesis, such as cleavage of the pore-forming protein DFNA5 [121].…”