PMID- 36142502 OWN - NLM STAT- MEDLINE DCOM- 20220926 LR - 20220928 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 18 DP - 2022 Sep 13 TI - Metabolic Adaptation as Potential Target in Papillary Renal Cell Carcinomas Based on Their In Situ Metabolic Characteristics. LID - 10.3390/ijms231810587 [doi] LID - 10587 AB - Metabolic characteristics of kidney cancers have mainly been obtained from the most frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic perturbances that affect metabolic adaptation possibilities of papillary renal cell carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR) and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC. The metabolic protein expression pattern, metabolite content, mTOR, and metabolic inhibitor sensitivity of renal carcinoma cell lines were also studied and compared with tubular epithelial cells, as "normal" control. We observed higher protein expressions of the "alternative bioenergetic pathway" elements, in correlation with the possible higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers correlates with the detected differences in metabolite ratios, as well. The lower lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the enzyme expression profiles, and the higher mitochondrial content also suggest increased importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally, PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors increased the effect of rapamycin in combined treatments. Our study revealed in situ metabolic differences in mTOR and metabolic protein expression patterns of human PRCC and CCRCC tissues as well as in cell lines. These underline the importance in the development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic drug combinations in PRCC therapy. FAU - Krencz, Ildiko AU - Krencz I AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Vetlenyi, Eniko AU - Vetlenyi E AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Danko, Titanilla AU - Danko T AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Petovari, Gabor AU - Petovari G AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Moldvai, Dorottya AU - Moldvai D AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Sztankovics, Daniel AU - Sztankovics D AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Raffay, Regina AU - Raffay R AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Meszaros, Katalin AU - Meszaros K AD - HAS-SE Momentum Hereditary Endocrine Tumour Syndromes Research Group, Hungarian Academy of Sciences and Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Sebestyen, Endre AU - Sebestyen E AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Vegso, Gyula AU - Vegso G AD - Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Ulloi ut 78, H-1082 Budapest, Hungary. FAU - Papay, Judit AU - Papay J AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. FAU - Sebestyen, Anna AU - Sebestyen A AUID- ORCID: 0000-0001-8814-4794 AD - Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, H-1085 Budapest, Hungary. LA - eng GR - UNKP_18-3-III-SE-24/New National Excellence Program of the Ministry of Human Capacities/ GR - NKFI-FK-128404/National Research, Development and Innovation Office/ GR - STIA-KFI-2020/Semmelweis Scientific and Innovation Fund/ GR - National Bionics Program, ED_17-1-2017-0009/National Research, Development and Innovation Fund of Hungary/ GR - FKIP/Higher Education Excellence Program at Semmelweis University/ GR - NVKP_16-1-2016-0004/Hungarian National Research, Development and Innovation Office (NKFIH)/ PT - Journal Article DEP - 20220913 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Citrates) RN - 0 (Lactates) RN - 0 (MTOR Inhibitors) RN - 0 (Malates) RN - 0 (Pyruvates) RN - 0 (RNA, Messenger) RN - 0RH81L854J (Glutamine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - *Carcinoma, Renal Cell/pathology MH - Citrates MH - Glutamine MH - Humans MH - *Kidney Neoplasms/metabolism MH - Lactates MH - MTOR Inhibitors MH - Malates MH - Pyruvates MH - RNA, Messenger MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases PMC - PMC9503093 OTO - NOTNLM OT - in situ expression and in vitro studies OT - mTOR OT - metabolism OT - papillary renal cell carcinoma COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/09/24 06:00 MHDA- 2022/09/28 06:00 PMCR- 2022/09/13 CRDT- 2022/09/23 01:24 PHST- 2022/06/28 00:00 [received] PHST- 2022/09/07 00:00 [revised] PHST- 2022/09/09 00:00 [accepted] PHST- 2022/09/23 01:24 [entrez] PHST- 2022/09/24 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] PHST- 2022/09/13 00:00 [pmc-release] AID - ijms231810587 [pii] AID - ijms-23-10587 [pii] AID - 10.3390/ijms231810587 [doi] PST - epublish SO - Int J Mol Sci. 2022 Sep 13;23(18):10587. doi: 10.3390/ijms231810587.