{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T14:47:29Z","timestamp":1770994049464,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA193675"],"award-info":[{"award-number":["R01 CA193675"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA222355"],"award-info":[{"award-number":["R01 CA222355"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Casey-Lee Ball Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Development of cancer, including renal cancer, is a major problem in immunosuppressed patients. The mTOR inhibitor Rapamycin (RAPA) is used as an immunosuppressive agent in patients with organ transplants and other immunological disorders; and it also has antitumorigenic potential. However, long-term use of RAPA causes reactivation of Akt, and ultimately leads to enhanced tumor growth. Honokiol (HNK) is a natural compound, which possesses both anti-inflammatory and antitumorigenic properties. In this study, we investigated the effect of a novel combination therapy using RAPA + HNK on allograft survival and post-transplantation renal tumor growth. We observed that it effectively modulated the expression of some key regulatory molecules (like Carabin, an endogenous Ras inhibitor; and Rubicon, a negative regulator of autophagy) that play important roles in tumor cell growth and survival. This combination induced toxic autophagy and apoptosis to promote cancer cell death; and was associated with a reduced expression of the tumor-promoting receptor tyrosine kinase AXL. Finally, we utilized a novel murine model to examine the effect of RAPA + HNK on post-transplantation renal tumor growth. The combination treatment prolonged the allograft survival and significantly inhibited post-transplantation tumor growth. It was associated with reduced tumor expression of Rubicon and the cytoprotective\/antioxidant heme oxygenase-1 to overcome therapeutic resistance. It also downregulated the coinhibitory programmed death-1 ligand, which plays major role(s) in the immune escape of tumor cells. Together, this combination treatment has a great potential to restrict renal tumor growth in transplant recipients as well as other immunosuppressed patients.<\/jats:p>","DOI":"10.1093\/carcin\/bgab126","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T20:20:46Z","timestamp":1640722846000},"page":"360-370","source":"Crossref","is-referenced-by-count":16,"title":["A Combination therapy using an mTOR inhibitor and Honokiol effectively induces autophagy through the modulation of AXL and Rubicon in renal cancer cells and restricts renal tumor growth following organ transplantation"],"prefix":"10.1093","volume":"43","author":[{"given":"Akash","family":"Sabarwal","sequence":"first","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Wedel","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaifeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3610-6942","authenticated-orcid":false,"given":"David","family":"Zurakowski","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samik","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn","family":"Flynn","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Briscoe","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"},{"name":"Transplant Research Program, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murugabaskar","family":"Balan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9177-6634","authenticated-orcid":false,"given":"Soumitro","family":"Pal","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"2022051911463570700_CIT0001","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1158\/1535-7163.MCT-17-1299","article-title":"Resistance to systemic therapies in clear cell renal cell carcinoma: mechanisms and management strategies","volume":"17","author":"Makhov","year":"2018","journal-title":"Mol. 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