Broad targeting of resistance to apoptosis in cancer

Abstract

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Keywords: Apoptosis; Apoptosis evasion; Autophagy; Necrosis; Nuclear transporters, natural chemopreventive agents.

Fig. 1

The apoptosis pathway: (A) The different paths that a cell can take during the activation of cell death. (B) Apoptosis can be triggered either by external receptor-dependent stimulus (extrinsic) or through internal (intrinsic) mitochondria-mediated signaling. The extrinsic pathway is initiated by the attachment of death receptors with their death initiating ligands, such as FASL, TRAIL or TNF. Consequently, an adaptor molecule, FADD also known as FAS-associated death domain protein, couples the death receptors and this subsequently leads to the activation of caspase-8. Activated caspase-8 can either directly cleave and activate caspase-7 or caspase-3, thereby promoting apoptosis. On the other hand the intrinsic pathway is modulated by the activation of BH3-only proteins sensing different types of cell stress, such as DNA damage or ER stress, and then activating BAX/BAK at mitochondrial outer membrane (MOM). MOM permeabilization (MOMP) leads to release of different apoptosis-mediating molecules, such as cytochrome c, which activates caspase-9. In turn, caspase-9 cleaves and activates caspase-3 and caspase-7, thus triggering apoptotic cell death. Both pathways interface at the point of caspase-3 activation. The formation of autophagosome formation requires activation of Beclin 1 which acts as a component of a multiprotein (PI3K) complex. The crosstalk between autophagy and apoptosis is mediated at least in part by the functional and structural interaction between Beclin 1 and the anti-apoptotic proteins BCL-2 and BCL-XL. Diverse apoptotic stimuli either intrinsic or extrinsic can lead to caspase-mediated cleavage of Beclin 1 rendering it ineffective as an autophagy inducer. The master tumor suppressor p53 has essential roles in both apoptosis and autophagy. At the transcriptional level, p53 upregulates BAX, PUMA and BID or reduces the expression of BCL-2, which antagonizes BAX. In addition to apoptosis, p53 can also induce autophagy through TOR inhibition and also through transcriptional activation of DRAM.