Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?

Abstract

In order to solve a jigsaw puzzle, one must first have the complete picture to logically connect the pieces. However, in cancer biology, we are still gaining an understanding of all the signaling pathways that promote tumorigenesis and how these pathways can be pharmacologically manipulated by conventional and targeted therapies. Despite not having complete knowledge of the mechanisms that cause cancer, the signaling networks responsible for cancer are becoming clearer, and this information is serving as a solid foundation for the development of rationally designed therapies. One goal of chemotherapy is to induce cancer cell death through the mitochondrial pathway of apoptosis. Within this review, we present the pathways that govern the cellular decision to undergo apoptosis as three distinct, yet connected puzzle pieces: (1) How do oncogene and tumor suppressor pathways regulate apoptosis upstream of mitochondria? (2) How does the B-cell lymphoma 2 (BCL-2) family influence tumorigenesis and chemotherapeutic responses? (3) How is post-mitochondrial outer membrane permeabilization (MOMP) regulation of cell death relevant in cancer? When these pieces are united, it is possible to appreciate how cancer signaling directly impacts upon the fundamental cellular mechanisms of apoptosis and potentially reveals novel pharmacological targets within these pathways that may enhance chemotherapeutic success.

Keywords: Apoptosis; BCL-2 family; BH3 mimetics; Cancer; Mitochondria; Oncogenes; Signaling; Tumor suppressors.

Figure 1

Piece #1: Tumor suppressor and oncogenic pathways converge on the mitochondrial pathway of apoptosis. Oncogenic (e.g., PI3K/AKT, RAS-MAPK, and Myc) and tumor suppressor pathways (e.g., p53, PTEN, and Rb) act at transcriptional and non-transcriptional levels to modulate cellular sensitivity to detect and repair stress, along with regulating the expression and function of downstream apoptotic proteins. Details are provided in the text.

Figure 2

Piece #2: The BCL-2 family controls BAK/BAX activation and MOMP. Pro-apoptotic BCL-2 family protein activation is triggered by extra- and intra-cellular signaling. De-repressor BH3-only proteins (green) prevent or disrupt inhibition by anti-apoptotic proteins (red). Direct activator BH3-only proteins (yellow) bind BAK and BAX (blue) to induce their homo-oligomerization and MOMP. Details are provided in the text.

Figure 3

Piece #3: Post-MOMP regulation of cell death. Pro-apoptotic proteins within the mitochondrial inter-membrane space (e.g., cytochrome c, SMAC, and Omi) are released after MOMP and directly regulate the activation of caspases and commitment to apoptosis. Details are provided in the text.