Chemoresistance in human ovarian cancer: the role of apoptotic regulators

Abstract

Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Recent evidence suggests that deregulation of key pro- and anti-apoptotic pathways is a key factor in the onset and maintenance of chemoresistance. Furthermore, the discovery of novel interactions between these pathways suggests that chemoresistance may be multi-factorial. Ultimately, the decision of the cancer cell to live or die in response to a chemotherapeutic agent is a consequence of the overall apoptotic capacity of that cell. In this review, we discuss the biochemical pathways believed to promote cell survival and how they modulate chemosensitivity. We then conclude with some new research directions by which the fundamental mechanisms of chemoresistance can be elucidated.

Figure 1

The Inhibitor of Apoptosis Proteins The human Inhibitor of Apoptosis Protein (IAP) family, originally characterized in baculovirus, currently consists of 6 members: X-Linked Inhibitor of Apoptosis Protein (Xiap), Human Inhibitor of Apoptosis Protein-1 and -2 (Hiap-1, -2), Neuronal Apoptosis Inhibitory Protein (Naip), survivin, and livin. Xiap is a 498-amino acid (~55 kDa) protein and is a potent inhibitor of caspases, including caspase-9, -7, and -3. Xiap contains three Baculoviral Inhibitory Repeat (BIR) domains, which are involved in direct inhibition of target caspases. Furthermore, Xiap contains a C-terminal RING-Zn Finger domain, which contains E3 Ubiquitin Ligase activity. In this regard, Xiap is known to ubiquitinate several target proteins, including caspase-3 and Smac/DIABLO. Xiap is also known to undergo autoubiqutination on Lys322 and Lys328. The role of Xiap's E3 activity in the regulation of apoptosis is unclear. Finally, Xiap is itself cleaved in a caspase-dependent manner during Fas-induced apoptosis. This cleavage occurs at the SESD sequence (amino acids 239–242), located between BIR domains 2 and 3, and results in the production of 2 ~30 kDa fragments of unknown function. Recent data from our laboratory suggests that Xiap is a determinant of cisplatin-mediated chemoresistance, and that the anti-apoptotic effects of Xiap are in part due to upregulation of the PI3K/Akt pathway and to suppression of p53-mediated cell death.

Figure 2

Hypothetical Model of Chemoresistance in Human Ovarian Cancer Cells. In a chemosensitive ovarian cancer cell (A), cisplatin increases p53 content, leading to upregulation of proteins promoting cell cycle arrest, such as p21, and of pro-apoptotic proteins such as Bax and Fas. This activates both the intrinsic (mitochondrial) and extrinsic (death-receptor) apoptotic pathways, the overall result of which is the activation of the execution caspase-3 (and -7, not shown). In these cells, cell survival mediators such as Xiap, Akt, and Flip (shown in red) are downregulated or are in their inactive state. Prohibitin may also play a role in inhibiting cell cycle progression through the Rb-E2F pathway by binding to Rb. Conversely, in a chemoresistant cell (B), increased p53 ubiquitination by MDM2 results in the maintenance of low levels of p53, despite the presence of cisplatin. Moreover, cisplatin fails to downregulate Xiap, thereby maintaining an active state of the PI3K/Akt pathway. In addition, binding of TNFR2 by TNFα leads to upregulation of FLIP through the NFκB pathway, thus inhibiting the pro-apoptotic actions of the cytokine through TNFR1. Overall, as a consequence of a failure to activate the caspase cascade in response to the chemotherapeutic agent, these cells have lost their capacity to undergo apoptosis, and thus became chemoresistant.