Mitochondria: gatekeepers of response to chemotherapy

Abstract

Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some cancers are sensitive to chemotherapy whereas others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies.

Keywords: apoptosis; chemotherapeutic window; chemotherapy; mitochondrial apoptotic priming.

Figure 1. A model for how pretreatment mitochondrial priming can affect response to pro-death signal

In unprimed cells, exogenous pro-apoptotic signals are bound and sequestered by unbound anti-apoptotic proteins. In primed cells, pro-apoptotic signals displace the BH3-only proteins bound to anti-apoptotic proteins which are then able to activate BAX/BAK.

Figure 2. Apoptotic priming can affect response to chemotherapy

(A) A cell that is primed for apoptosis is more likely to undergo cell death in response to chemotherapy than an unprimed cell. (B) A cell that is primed for apoptosis nonetheless does not undergo cell death in response to a targeted agent if it does not exhibit a dependence on the target of the therapy. A cell that is unprimed, but exhibits a strong dependence on the target of the therapy may unleash sufficient pro-apoptotic signaling to trigger apoptosis. (C) Two cells that exhibit similar dependence on the target of the therapy may have different treatment outcomes based on levels of apoptotic priming present in cells prior to therapy. (D) A cell that is unprimed yet exhibits dependence on the target of the therapy may become primed in response to the therapy if apoptosis is not triggered directly by the single agent. An additional bolus of pro-apoptotic signaling, here provided by treatment with a cytotoxic chemotherapy which would not kill an unprimed cell, is sufficient to trigger apoptosis.

Figure 3

Apoptotic priming varies between tumors and healthy tissues and provides a window for chemotherapeutic efficacy.