Raptinal bypasses BAX, BAK, and BOK for mitochondrial outer membrane permeabilization and intrinsic apoptosis

Sina Heimer,Klaus Schulze-Osthoff,Gertrud Knoll,Martin Ehrenschwender

doi:10.1038/s41419-019-1790-z

Abstract

Most antineoplastic chemotherapies eliminate cancer cells through activation of the mitochondria-controlled intrinsic apoptotic pathway. Therein, BAX, BAK, and/or BOK function as the essential pore-forming executioners of mitochondrial outer membrane permeabilization (MOMP). The activation threshold of BAX and BAK also correlates inversely with the required strength of an apoptotic stimulus to induce MOMP and thereby effectively determines a cell’s readiness to undergo apoptosis. Consequently, the ‘gatekeepers’ BAX and BAK emerged as therapeutic targets, but functional or genetic loss renders BAX/BAK-targeting strategies prone to fail. Here, we show that the small molecule Raptinal overcomes this limitation by triggering cytochrome c release in a BAX/BAK/BOK-independent manner. Raptinal exerts a dual cytotoxic effect on cancer cells by rapid activation of the intrinsic apoptotic pathway and simultaneous shutdown of mitochondrial function. Together with its efficacy to eliminate cancer cells in vivo, Raptinal could be useful in difficult-to-treat cancer entities harboring defects in the intrinsic apoptosis pathway.

Highlights

Most antineoplastic chemotherapies rely on activation of the mitochondria-controlled intrinsic apoptotic pathway to eliminate cancer cells[1]
Raptinal is a notable exception as (1) the mitochondrial priming of target cells does not enhance its cytotoxic activity (Fig. 2a) and (2) the cytochrome c release and mitochondrial outer membrane permeabilization (MOMP) occur in a BAX/BAK/BOK-independent manner (Figs. 4b, c, 5f, and 6f)
Our data argue against a decisive role for BOK in Raptinal-induced MOMP (Fig. 6)

Summary

Introduction

Most antineoplastic chemotherapies rely on activation of the mitochondria-controlled intrinsic apoptotic pathway to eliminate cancer cells[1]. The key effector proteins for intrinsic apoptosis, BAX, BAK, and/or BOK, form (once activated) pores in the outer mitochondrial membrane and cause mitochondrial outer membrane permeabilization (MOMP)[2,3,4]. Subsequent cytochrome c release allows assembly of the ‘apoptosome’ complex[5]. This scaffold fosters activation of caspase-9, the prototypic initiator caspase of the intrinsic apoptotic pathway. Caspase-9 in turn activates the effector caspases 3 and 7, both executioners of apoptosis[6]. MOMP initiates the cascadelike activation of caspases. Concomitant loss of mitochondrial transmembrane potential severely compromises

Methods

Results

Conclusion