Abstract 1009: Metabolic reprogramming discriminates aggressive vs. slowly growing preneoplastic lesions at early stages of HCC development

Abstract

Introduction and aim: Among the several changes underlying metabolic reprogramming of cancer cells, increased glucose utilization and its uncoupling from oxygen availability is a well-established phenomenon and has been recognized as a hallmark of cancer. To what extent these metabolic changes are important for the progression of slow growing tumors and whether a metabolic rewiring occurs in the very early stages of neoplastic progression represent key questions on the significance of these metabolic alterations in cancer. Here, we compared the metabolic features of preneoplastic hepatic lesions with those of advanced hepatocellular carcinomas (HCCs) and of proliferating liver, following partial hepatectomy (PH). Materials and Methods: Expression levels, activity and modulation of several enzymes with key roles in glycolysis, pentose phosphate pathway (PPP) and oxidative phosphorylation (OXPHOS) were assessed in preneoplastic hepatic lesions and HCC, induced in rats exposed to the Resistant-Hepatocyte (R-H) model. In vitro experiments were performed on HCC cells obtained by perfusion of HCC-bearing rats. Expression of metabolic genes was also investigated in two different cohorts of human patients carrying HCC. Results and discussion: A switch from OXPHOS to PPP was observed in very early preneoplastic lesions generated 10 weeks after the treatment with DENA. Notably, this metabolic reprogramming was observed only in the most aggressive preneoplastic lesions, characterized by positivity for cytokeratin 19 (CK-19+). PPP induction, shown by a strong increase in the expression and activity of glucose 6-phosphate dehydrogenase (G6PD) was supported both by inhibition of pyruvate kinase activity and by TP53-inducible glycolysis and apoptosis regulator (TIGAR) induction. Importantly, such metabolic rewiring was not observed in normal hepatocytes, undergoing proliferation following 2/3 partial hepatectomy (PH). Activation of the NRF2/KEAP1 pathway and down-regulation of miR-1 accompanied the metabolic reprogramming in CK-19+ preneoplastic lesions. Accordingly, NRF2 silencing decreased G6PD and increased miR-1 expression, consequently inhibiting PPP, while forced expression of miR-1 downregulated G6PD expression in HCC cells. Finally, an inverse correlation between miR-1 and its target gene G6PD was found in human HCC patients. Conclusion: These results demonstrate that metabolic reprogramming takes place at early stages of hepatocarcinogenesis and is likely the consequence of the concomitant activation of the NRF2-KEAP1 pathway. Citation Format: Marta A. Kowalik, Giulia Guzzo, Andrea Morandi, Andrea Perra, Silvia Menegon, Ionica Masgras, Elena Trevisan, Maria M. Angioni, Francesca Fornari, Luca Quagliata, Giovanna M. Ledda-Columbano, Laura Gramantieri, Luigi Terracciano, Silvia Giordano, Paola Chiarugi, Andrea Rasola, Amedeo Columbano. Metabolic reprogramming discriminates aggressive vs. slowly growing preneoplastic lesions at early stages of HCC development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1009.

Protein Allostery and Ligand Design: Computational Design Meets Experiments to Discover Novel Chemical Probes

“…Second-generation molecules revert TRAP1dependent SDH inhibition. We have previously reported that TRAP1 downregulates the enzymatic activity of SDH in various tumor cell types, 33,36,53,[69][70][71][72] and that this inhibition can be overturned by allosteric TRAP1 inhibition. 33,36,72 We have also shown that SDH inhibition is favored by ERK-dependent TRAP1 phosphorylation in tumor cells endowed with hyperactivation of the Ras/ERK signaling pathway, such as cellular models of malignant peripheral nerve sheath tumors (MPNST), where TRAP1 has been identified as an important determinant of their pro-neoplastic features.…”

“…TRAP1 overexpression is associated with several tumor types, including prostate, breast and neurofibromatosis NF1 cancer. [51][52][53] In spite of these observations, induction of TRAP1 levels is somewhat disputed in certain tumor settings, such as kidney cancer. 54,55 These data highlight the complex and only partially understood role of TRAP1 in cancer progression and underline the necessity for specific targeting of its activities.…”