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Significance: Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reduction–oxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Recent Advances: Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Critical Issues: Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. Future Directions: In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field. [ABSTRACT FROM AUTHOR]

Ras-related GTP binding (Rag) GTPases are required to activate mechanistic target of rapamycin complex 1 (mTORC1), which plays a central role in cell growth and metabolism and is considered as one of the most important oncogenic pathways. Therefore, Rag GTPases have been speculated to play a pro-cancer role via mTOR induction. However, aside from stimulation of mTOR signaling, firm links connecting Rag GTPase activity and their downstream effectors with cancer progression, remain largely unreported. In this study, we reported a novel link between RagB/C and a known oncoprotein phosphatase of regenerating liver-3 (PRL-3) by screening 22 pairs of tumors and their adjacent normal tissues from gastric, liver and lung cancers, and validating our findings in cancer cell lines with ectopic RagB/C expression. RagB/C was found to enhance PRL-3 stability by modulating two major cellular protein degradation pathways: lysosomal-autophagy and ubiquitin-proteasome system (UPS). Functionally, we identified the correlation between RagB/C expression with poor clinical outcomes in breast or colon cancer patients who also showed low PRL-3 mRNA expression from data retrieved from TCGA datasets, highlighting the potential relevance of Rag GTPase and PRL-3 mRNA in combination as a prognostic clinical biomarker. • RagB/C is upregulated in tumor tissues and correlates with PRL-3 expression. • RagB/C promotes PRL-3 stability, rather than enhances PRL-3 protein synthesis. • RagB/C inhibits both autophagy and ubiquitin-proteasome degradation of PRL-3. • Novel lysosomal localization and ubiquitination of PRL-3 has been identified. • RagB/C correlates with poor survival in cancer patients expressing low PRL-3 mRNA. [ABSTRACT FROM AUTHOR]