Novel roles of apoptotic caspases in tumor repopulation, epigenetic
reprogramming, carcinogenesis, and beyond
Andrew K. Lee
Springer Science+Business Media, LLC, part of Springer Nature 2018
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 tumorige-
nicity 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.
Keywords Apoptotic caspases
Cancer stem cells
1 Apoptotic caspases, the established
Apoptosis is a process for multicellular organisms to get rid of
damaged or unwanted cells. Apoptotic cells die in an orderly
fashion with features of pyknosis, karyorrhexis, and karyolysis;
no inflammation follows, which is a main characteristic that sets
it apart from necrosis. There is no disturbance of neighboring
cells, as apoptotic bodies are taken up by macrophages.
Caspases, a family of proteases that are pivotal executioners
of apoptosis, comprise of the initiators and the effectors .
The initiator caspases include caspase-2, -8, -9, and -10, and
the effector caspases include caspase-3, -6, and -7. The apopto-
tic process in mammalian cells is mediated through either the
intrinsic or the extrinsic pathway. Briefly, the intrinsic pathway
is usually activated as a result of pro-apoptotic signals that
activate several proteins inside the mitochondria to be released
into the cytoplasm. A key mitochondrial protein released being
cytochrome c, which binds to APAF1 that causes APAF1 to
further bind to ATP/dATP, forming the apoptosome . The
apoptosis then recruits and activates caspase 9. Of note, addi-
tional proteins that were released from the mitochondria in
addition to cytochrome c include apoptosis-inducing factor
(AIF), endonuclease G, high temperature requirement protein
A2, second mitochondria-derived activator of caspase, and di-
rect inhibitor of apoptosis binding protein with low pH .
Activation of caspase-9 leads to caspase-3 activation, which
is the executioner caspase that kills the host cell.
On the other hand, the extrinsic pathway is initiated by
extracellular signals. Extracellular molecules, such as the
well-known Fas Ligand binds to the Fas receptor on cellular
surface . Upon binding, cytosolic factors caspase-8 and
FADD associate with the activated homotrimeric receptor to
form the death-inducing signaling complex or DISC .
Subsequently, DISC cleaves caspase 8 and allows it to activate
the effector caspase 3, which leads to dismantling of critical
cellular infrastructure and eventual cell death.
* Chuan-Yuan Li
Duke University School of Medicine, Durham, NC, USA
Department of Pharmacology and Cancer Biology, Duke University
Medical Center, Box 3135, Med Ctr, Durham, NC 27710, USA
Department of Dermatology, Duke University Medical Center, Box
3135, Med Ctr, Durham, NC 27710, USA
Cancer and Metastasis Reviews