Pathophysiology of Cancer Cell Death
Summary of Key Points
• Regulated cell death can occur via extrinsic apoptosis, intrinsic apoptosis, or regulated necrosis. Autophagy operates as a bona fide cell death mechanism in a few (mostly developmental) settings.
• Oncogenesis results from multiple molecular alterations, one of which frequently impairs the ability of cancer cells to die in response to exogenous or endogenous signals.
• Several oncoproteins and oncosuppressor proteins regulate the molecular machinery for apoptotic or necrotic cell death either directly or in an indirect fashion.
• Targeting deregulated cell death signaling pathways in cancer is a clinical reality and underlies promising approaches for the development of novel anticancer regimens.
1. Which of the following molecular alterations may be common among patients with lymphoma?
A A translocation between chromosome 14 and chromosome 19, resulting in the overexpression of BAX
B A loss-of-function point mutation in AKT
C An amplification in the chromosomal region 12q13-14, encompassing HDM2
2. The detection of a point mutation in TP53 that negatively affects p53-regulated gene transactivation would prompt for:
A The administration of a hypothetical Food and Drug Administration (FDA)-approved HDM2 inhibitor
3. Which of the following options may constitute the basis for the development of novel anticancer regimens?
A The screening of a combinatorial chemical library for the identification of RIP3K activators
4. Which of the following statements is best supported by experimental evidence?
1. Answer: C. BAX overexpression is expected to counteract oncogenesis, similar to inactivating mutations in AKT. Conversely, the amplification of HDM2 is relatively common among tumors, leading to the functional inactivation of the p53 system.
2. Answer: C. Increasing the levels of mutant p53 by using HDM2 inhibitors is expected to be useless in the presence of inactivating mutations of p53. Along similar lines, the use of DNA-damaging agents presumably would yield poor results because these compounds usually function by activating p53. Conversely, Gendicine would lead to the restoration of a functional p53 system, perhaps exerting direct anticancer effects or rendering cancer cells responsive to chemotherapy.
3. Answer: A. Inhibition of BAX or caspases appears to be therapeutically useful in conditions featuring excessive cell death, such as ischemia or neurodegeneration. Conversely, novel activators of RIPK3 that would selectively trigger the necrotic demise of cancer cells might be very promising, because cancer cells often are intrinsically resistant to the therapeutic induction of apoptosis.
4. Answer: B. Although both death receptors and dependence receptors trigger extrinsic apoptosis, they not only respond to different conditions but they also engage distinct signaling cascades. Still, both death receptors and dependence receptors eventually lead to the proteolytic activation of caspase-3.
