In 1998, Voelkel and colleagues published a visionary review highlighting apparent similarities between pulmonary arterial hypertension (PAH) and cancer (1). The cancer concept of PAH was initially fueled by the identification of a monoclonal expansion of endothelial cells in lesions of patients with idiopathic PAH (2), but has since been complemented by other characteristic features shared by cancer and PAH cells alike, such as the frequent occurrence of DNA damage, upregulation of the antiapoptotic protein survivin, and the metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis (the Warburg effect), all of which are considered to contribute to the cancer-like phenotype with exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells in PAH (3, 4). The cancer hypothesis has fueled the translation of concepts and therapies originally established in cancer research toward a better understanding and treatment of PAH disease. Yet, although some anticancer drugs (e.g., tyrosine kinase inhibitors) have proved effective in preclinical or clinical trials, their clinical utility has been limited by severe adverse events due to off-target effects on non-PAH cells (3, 5).
In a study published in this issue of the Journal, Boucherat and colleagues (pp. 90–103) translate another paradigm of increased cellular resistance to stress from cancer to PAH, with the unique perspective that therapies based on this concept may exclusively target PAH but not healthy, nonaffected cells (6). In their study, the authors focused on HSP90 (heat shock protein 90), a molecular chaperone that is ubiquitously expressed in the cytosol, where it assists in the folding and stabilization of other proteins. Cancer cells hijack this evolutionarily conserved system to protect oncoproteins, which has recently fueled interest in HSP90 inhibitors as potential anticancer drugs. In tumor cells, but not in normal tissue, HSP90 is also present in considerable amounts in mitochondria, where it antagonizes the function of the proapoptotic molecule cyclophilin D (7) and maintains energy production under low-nutrient conditions (8). Selective accumulation of HSP90 in tumor mitochondria requires HIF-1α (hypoxia-inducible factor 1α) (8), a transcription factor with key relevance in PAH, yet the exact molecular mechanisms underlying the translocation of HSP90 into mitochondria and the specificity of these mechanisms for cancer cells remain unknown.
In an elegant series of translational experiments, Boucherat and colleagues found that similarly to cancer cells, pulmonary artery smooth muscle cells (PASMCs) from patients with PAH contained considerable amounts of mitochondrial HSP90, whereas HSP90 was confined to the cytosol in PASMCs from subjects without PAH (6). Notably, HSP90 was also increased in the cytosolic fraction of PAH-PASMCs as compared with control cells. However, cytosolic abundance is likely not the main reason for mitochondrial accumulation of HSP90, as HSP90 translocation to mitochondria could also be induced by hypoxia (potentially via HIF-1α [see above]?) or oxidative stress in less than 2 hours. Analogously to its documented role in cancer cells, mitochondrial HSP90 conferred important protection against increased cell stress in PAH-PASMCs, in that it induced expression of key proteins involved in mitochondrial DNA replication and repair. This resulted in reduced mitochondrial DNA damage and increased stability, and maintained cellular bioenergetics by increasing the glycolytic capacity according to the Warburg effect. These effects were specific to mitochondrial HSP90, as they could be blocked by small molecules designed to selectively target mitochondrial HSP90, called Gamitrinib (GA mitochondrial matrix inhibitor) (9), but not by two non–mitochondrially targeted cytosolic HSP90 inhibitors.
Gamitrinib accumulates in mitochondria of human tumor cells, where they inhibit HSP90 activity, causing rapid tumor death and inhibiting the growth of xenografted human cancer cell lines in mice via a “mitochondriotoxic” mechanism (9). Due to their specific effect on mitochondrial HSP90 and the selective accumulation of HSP90 in mitochondria of cancer or cancer-like cells, Gamitrinib has been reported to lack toxic effects on normal cells or tissues, and to not affect HSP90 homeostasis in cellular compartments other than mitochondria (9). Analogously, Boucherat and coworkers found that Gamitrinib reduced the proliferation and viability, and increased apoptosis of PAH-PASMCs, with no detectable effects on control PASMCs (6). These effects of Gamitrinib translated into successful treatment outcomes in two rat models of pulmonary hypertension, with improved pulmonary hemodynamics, reduced vascular remodeling, and attenuated PASMC proliferation in the absence of detectable systemic side effects.
Given the ongoing clinical development of Gamitrinib as a first-in-class subcellularly directed anticancer agent, the results by Boucherat and coworkers may pave the way to an innovative therapy for PAH that selectively targets hyperproliferative cells with limited or no off-target effects. Irrespective of this exciting potential, key questions remain to be resolved before such an approach can be translated to the clinic. First, although mitochondrial HSP90 is not expressed in most normal tissues, it has been found in the brain and testis, and is actively imported into normal brain mitochondria via a valinomycin-dependent mechanism (6). Whether this poses a potential risk in Gamitrinib therapy is unclear, as we lack an in-depth preclinical analysis of Gamitrinib’s effects on neurological, cognitive, and reproductive functions. In addition, the demonstrated mitochondrial accumulation of HSP90 in non-PAH cells in response to hypoxia may indicate a risk of off-target effects in hypoxic tissues. Second, vascular remodeling in PAH has both hyperproliferative (in the intima and media of small- and medium-sized arteries) and obliterative (in the microvasculature) features (10), with Gamitrinib targeting only the former. Further, the mitochondrial accumulation of HSP90 observed in PASMCs from patients with PAH was not detectable in corresponding pulmonary artery endothelial cells, suggesting that Gamitrinib may have little or no effect on intimal hyperplasia, an important contributor to vascular remodeling in PAH (11). Although the in vivo data presented by Boucherat and coworkers clearly show a hemodynamic benefit, one should keep in mind that the pathophysiology of PAH is more complex than PASMC hyperproliferation alone. Finally, in addition to HSP90, mitochondria also contain a unique HSP90 paralog, TRAP-1 (tumor necrosis factor receptor–associated protein 1), which is generated from a precursor protein containing a mitochondrial import sequence (12). TRAP-1 and HSP90 display 60% homology at the mRNA level, yet TRAP-1 has a lower molecular weight of approximately 75 kD (13). Like HSP90, TRAP-1 is enriched in mitochondria of neoplastic cells as compared with control cells, but unlike HSP90, it is absent from the cytosol of both tumor and normal cells. TRAP-1 closely interacts with Hsp90 in a chaperone network to antagonize the proapoptotic properties of cyclophilin D (14) and to regulate mitochondrial bioenergetics in tumor cells, with a profound impact on neoplastic growth (13). Similarly to mitochondrial HSP90, Gamtrinib inhibits the ATPase activity of TRAP-1 (12), and thus their beneficial effects in PAH may be equally attributable to inhibition of mitochondrial HSP90, TRAP-1, or both—this remains to be clarified. In either case, however, subcellular targeting of HSP90 (and/or TRAP-1) may allow us to better exploit the nodal properties of these chaperones in PAH therapies, with the aim of combining increased effectiveness with reduced adverse effects.
| 1. | Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114(3, Suppl):225S–230S. |
| 2. | Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927–934. |
| 3. | Boucherat O, Vitry G, Trinh I, Paulin R, Provencher S, Bonnet S. The cancer theory of pulmonary arterial hypertension. Pulm Circ 2017;7:285–299. |
| 4. | Guignabert C, Tu L, Le Hiress M, Ricard N, Sattler C, Seferian A, et al. Pathogenesis of pulmonary arterial hypertension: lessons from cancer. Eur Respir Rev 2013;22:543–551. |
| 5. | Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant 2015;34:1366–1375. |
| 6. | Boucherat O, Peterlini T, Bourgeois A, Nadeau V, Breuils-Bonnet S, Boilet-Molez S, et al. Mitochondrial HSP90 accumulation promotes vascular remodeling in pulmonary arterial hypertension. Am J Respir Crit Care Med 2018;198:90–103. |
| 7. | Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ, Altieri DC. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 2007;131:257–270. |
| 8. | Chae YC, Angelin A, Lisanti S, Kossenkov AV, Speicher KD, Wang H, et al. Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 2013;4:2139. |
| 9. | Kang BH, Plescia J, Song HY, Meli M, Colombo G, Beebe K, et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J Clin Invest 2009;119:454–464. |
| 10. | Chaudhary KR, Taha M, Cadete VJ, Godoy RS, Stewart DJ. Proliferative versus degenerative paradigms in pulmonary arterial hypertension: have we put the cart before the horse? Circ Res 2017;120:1237–1239. |
| 11. | Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:261–272. |
| 12. | Altieri DC, Stein GS, Lian JB, Languino LR. TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 2012;1823:767–773. |
| 13. | Masgras I, Sanchez-Martin C, Colombo G, Rasola A. The chaperone TRAP1 as a modulator of the mitochondrial adaptations in cancer cells. Front Oncol 2017;7:58. |
| 14. | Siegelin MD. Inhibition of the mitochondrial Hsp90 chaperone network: a novel, efficient treatment strategy for cancer? Cancer Lett 2013;333:133–146. |
Originally Published in Press as DOI: 10.1164/rccm.201801-0200ED on February 13, 2018
Author disclosures are available with the text of this article at www.atsjournals.org.