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Pathways that mediate oncogene-induced alterations in cellular metabolism are emerging as attractive new targets for enhancing apoptotic responses to cancer chemotherapeutics. Cancer cells frequently reprogram cellular metabolism in parallel with activation of cell cycle progression to support the demands of rapid cell growth and mitogenesis1. The benefits of altered metabolism for cancer cells are not fully understood, but include rapid ATP production, increased production of macromolecular building blocks, and increased survival in oxygen-limiting conditions. What is clear, however, is that metabolic reprogramming renders cancer cells hypersensitive to interruptions in the availability or the metabolism of glucose2. Multiple groups are extending these observations to identify oncogene-induced alterations in metabolic pathways beyond glycolysis, finding potential therapeutic targets in the pathways that control amino acid metabolism, fatty acid synthesis, and others3-7. The goal is to identify approaches to interrupt cancer cell metabolism that can be combined with existing chemotherapeutics to enhance apoptotic responses in cancer cells.
In the current issue of Cancer Biology and Therapy, Wang et al. expand the options for combining metabolic interventions with genotoxic chemotherapeutics by demonstrating that the stomatin-like protein 2 (SLP-2) coordinates bioenergetics and apoptosis8. SLP-2 (also known as STOML2 and HSPC108) is a mitochondrial protein that is overexpressed in carcinomas of the esophagus, lung, endometrium and other tissues9. SLP-2 is tightly associated with the mitochondrial inner membrane but resides within the intermembrane space, between the inner and outer mitochondrial membranes10. This is the same compartment that contains the apoptogenic factors cytochrome c and SMAC, as well as the membrane fusion regulator Optic Atrophy1 (OPA1) (Figure 1). SLP-2 physically associates with another regulator of mitochondrial outer membrane fusion known as mitofusin 2 (Mfn2)11. Wang et al. demonstrate that SLP-2 is a regulator of mitochondrial membrane potential and ATP production, functions that may be mediated by Mfn-2, OPA1, or other proteins that co-localize with or bind to SLP-2.
OPA1 and Mfn2 are members of a family of dynamin-like GTPase proteins that regulate mitochondrial dynamics. Additional members of the family are Mfn1, a close structural homologue of Mfn2 that regulates mitochondrial outer membrane fusion, and Dynamin Related Protein 1 (DRP1), a regulator of mitochondrial fission12. Mitochondrial dynamics are intricately linked to the regulation of apoptosis: activation of apoptosis is temporally associated with the induction of mitochondrial fission, which converts the tubular mitochondrial network into an assembly of isolated mitochondria. Inactivation of DRP1 is sufficient to block mitochondrial fission and delay cytochrome c release13, while overexpression of the mediators of mitochondrial fusion, Mfn1, Mfn2, and OPA1, is sufficient to delay apoptosis14, 15. Interestingly, apoptosis regulation by OPA1 and DRP1 has recently been shown to be independent of the regulation of mitochondrial dynamics16, 17. OPA1 regulation of cytochrome c release occurs even when mitochondrial fusion is genetically blocked, demonstrating a fusion-independent activity of OPA1 in regulating apoptosis16. OPA1 regulates cytochrome c release by modifying the structure of cristae junctions, which can restrict the exit of cytochrome c from mitochondrial cristae16, 21. Similarly, genetic and pharmacologic approaches have demonstrated that DRP1 regulation of apoptosis is independent of mitochondrial dynamics18-20.
The localization of SLP-2 to the mitochondrial intermembrane space and its interaction with Mfn2 may suggest that SLP-2 participates in the regulation of mitochondrial fusion. However, RNAi knockdown of SLP-2 does not alter mitochondrial dynamics in healthy cells, in contrast to the effects of Mfn2 deficiency8, 22. Instead SLP-2 appears to be a critical regulator of mitochondrial responses to stress stimuli, including pro-apoptotic responses to cycloheximide and UV irradiation. In a report recently published in The EMBO Journal, Tondera and colleagues demonstrated an anti-apoptotic role for SLP-2 in cells stressed with cycloheximide and UV irradiation22. In response to pro-apoptotic stimuli, SLP-2 was essential for preserving long isoforms of OPA1 by restraining proteolytic processing, permitting an adaptive response characterized by mitochondrial hyperfusion, which requires uncleaved OPA1 isoforms. Based on these results, SLP-2 can be viewed as a regulator of OPA1 apoptosis control independent of basal control of mitochondrial dynamics.
The study by Wang et al. in this issue of Cancer Biology and Therapy extends the functional relevance of SLP-2 by demonstrating its protective effect in cells treated with cancer chemotherapeutics. Using esophageal carcinoma cells, Wang et al. report that SLP-2 knockdown induced a decline in mitochondrial membrane potential and ATP production, which was associated with decreased cell motility and S phase arrest. It is important to note that there is some variability in the effect of SLP-2 knockdown on mitochondrial membrane potential: two groups have observed decreased membrane potential8, 11, while another reported no change22. However, there is agreement in the role of SLP-2 in the regulation of apoptosis: SLP-2 knockdown alone has little effect on cell viability in otherwise healthy cells8, 22. Instead, SLP-2 regulation of apoptosis is only revealed upon stressing the cells with cancer chemotherapeutics. Wang et al. report that esophageal carcinoma cells exhibited enhanced apoptotic responses to cisplatin, adriamycin or camptothecin in SLP-2-knockdown conditions as compared to controls. SLP-2 expression correlates with invasive carcinoma, suggesting a novel molecule that contributes to the chemoresistance of advanced stages of carcinoma.
The development of novel cancer chemotherapeutics inevitably becomes a search for new targets that can be exploited to preferentially induce apoptosis in transformed cells. The requirement for selectivity in apoptosis induction in transformed cells is often the key hurdle in determining the potential benefit of a new target or new approach in cancer chemotherapy. Genotoxic chemotherapeutics such as cisplatin reactivate dormant apoptosis mechanisms preferentially in proliferating cells, thus exploiting the pro-mitogenic effects of oncogenic mutations. The results from the study by Wang et al. suggest that metabolic alterations induced by SLP-2 inactivation may enhance the therapeutic window for genotoxic cancer chemotherapeutics.
The identification of SLP-2 as a link between mitochondrial stress responses, bioenergetics and apoptosis is a significant advance in identifying the pathways that link mitochondrial dynamics to apoptotic responses. Currently, upstream pathways linking mitochondrial stress to SLP-2 function are not known, and the metalloproteases that mediate SLP-2 regulation of OPA1 processing remain to be identified. An important question is whether SLP-2 regulates cytochrome c release kinetics, which can be regulated through effects on OPA1 and cristae junction conformation. Mechanistically, there is a need to define SLP-2 regulation of mitochondrial bioenergetics, and whether bioenergetic effects are upstream, parallel to, or a consequence of alterations in mitochondrial conformation and cytochrome c release. Such experiments will help in further defining this pathway and determining optimal targets for cancer therapy. As mechanistic details become available, it will be important to relate the results back to cancers marked by SLP-2 overexpression and the sensitivity of these cancers to genotoxic chemotherapeutics. Though the molecule is only beginning to be understood, there are promising possibilities for improving cancer therapy through manipulation of the SLP-2 apoptosis control pathway.
We thank Dr. David Hildeman (Cincinnati Children's Hopsital) for comments on the manuscript, and we thank Glenn Doermann for artwork. We gratefully acknowledge research support from the National Cancer Institute and the American Cancer Society.