A 54-year-old woman with high-grade serous ovarian carcinoma is initiated on systemic induction therapy with carboplatin and paclitaxel. Following two cycles of treatment, imaging demonstrates a significant reduction in her tumor burden. The platinum-based component of her regimen exerts its primary antineoplastic effect by triggering the intrinsic apoptotic pathway in rapidly dividing cells.
Arrange the following cellular and molecular events in the correct chronological sequence to describe this mechanism of tumor cell death, beginning with the initial pharmacologic insult and ending with the activation of the executioner phase.
- 1Formation of covalent intra-strand and inter-strand crosslinks within nuclear DNA
- 2Activation of sensor kinases and subsequent stabilization of the p53 tumor suppressor protein
- 3Transcriptional upregulation of pro-apoptotic proteins and oligomerization of Bax and Bak
- 4Permeabilization of the outer mitochondrial membrane and efflux of cytochrome c
- 5Binding of cytochrome c to APAF-1 and sequential cleavage of procaspase-9
Answer
The correct sequence is: DNA crosslinking → p53 stabilization → Bax/Bak oligomerization → Cytochrome c efflux → Apoptosome assembly.
The intrinsic (mitochondrial) pathway of apoptosis is a highly regulated sequence. Platinum-based chemotherapies initiate this by creating DNA crosslinks. This nuclear damage is sensed and leads to the stabilization of p53. p53 then acts on the mitochondria by upregulating pro-apoptotic proteins, causing Bax and Bak to oligomerize and form pores in the outer mitochondrial membrane. These pores allow cytochrome c to escape into the cytosol, where it binds to APAF-1 to form the apoptosome, ultimately activating caspase-9.
Step-by-Step Solution
Key Concept
The intrinsic apoptotic pathway is sequentially initiated by DNA damage, mediated by p53 stabilization, executed at the mitochondrion via Bax/Bak and cytochrome c, and finalized in the cytosol by apoptosome formation.
Estimated Time:1m 30s