{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:52:50Z","timestamp":1779119570971,"version":"3.51.4"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2014,12,1]],"date-time":"2014-12-01T00:00:00Z","timestamp":1417392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lymphangioleiomyomatosis (LAM) is a female-predominant cystic lung disease that can lead to respiratory failure. LAM cells typically have inactivating tuberous sclerosis complex 2 (TSC2) mutations and mammalian target of rapamycin (mTOR) complex (mTORC) 1 activation. Clinical response to the mTORC1 inhibitors has been limited, prompting a search for additional therapy for LAM. In this study, we investigated the impact of TSC2 on the expression of poly (ADP-ribose) polymerase (PARP)-1 that initiates the DNA repair pathway, and tested the efficacy of PARP1 inhibitors in the survival of TSC2-deficient (TSC2\u2212) cells. We analyzed publicly available expression arrays of TSC2\u2212 cells and validated the findings using real-time RT-PCR, immunoblotting, and immunohistochemistry. We examined the impact of rapamycin and Torin 1 on PARP1 expression. We also tested the effect of PARP1 inhibitors, 8-hydroxy-2-methylquinazoline-4-one and 3,4-dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline, on the survival of TSC2\u2212 cells. We identified the up-regulation of PARP1 in TSC2\u2212 cells relative to cells in which wild-type TSC2 has been reintroduced (TSC2-addback [TSC2+] cells). The transcript levels of PARP1 in TSC2\u2212 cells were not affected by rapamycin. PARP1 levels were increased in TSC2\u2212 cells, xenograft tumors of rat-derived TSC2\u2212 cells, renal cystadenomas from Tsc2+\/\u2212 mice, and human LAM nodules. RNA interference of mTOR failed to reduce PARP1 levels. Proliferation and survival of TSC2\u2212 cells was reduced in response to PARP1 inhibitor treatment, more so than TSC2+ cells. TSC2\u2212 cells exhibit higher levels of PARP1 relative to TSC2+ cells in an mTOR-insensitive manner. PARP1 inhibitors selectively suppress the growth and induce apoptosis of TSC2\u2212 cells from patients with LAM. Targeting PARP1 may be beneficial in the treatment of LAM and other neoplasm with mTORC1 activation.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0033oc","type":"journal-article","created":{"date-parts":[[2014,5,29]],"date-time":"2014-05-29T11:11:52Z","timestamp":1401361912000},"page":"738-749","source":"Crossref","is-referenced-by-count":9,"title":["Rapamycin-Resistant Poly (ADP-Ribose) Polymerase-1 Overexpression Is a Potential Therapeutic Target in Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"51","author":[{"given":"Yang","family":"Sun","sequence":"first","affiliation":[{"name":"Brigham and Women\u2019s Hospital\/Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Gallacchi","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital\/Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik 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