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Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC., (© 2023. The Author(s).)

Although the Wnt/β-catenin pathway plays a central role in the carcinogenesis and maintenance of colorectal cancer (CRC), attempts to target the pathway itself have not been very successful. MyD88, an adaptor protein of the TLR/IL-1β signaling, has been implicated in the integrity of the intestines as well as in their tumorigenesis. In this study, we aimed to clarify the mechanisms by which epithelial MyD88 contributes to intestinal tumor formation and to address whether MyD88 can be a therapeutic target of CRC. Conditional knockout of MyD88 in intestinal epithelial cells (IECs) reduced tumor formation in Apc +/Δ716 mice, accompanied by decreased proliferation and enhanced apoptosis of tumor epithelial cells. Mechanistically, the MyD88 loss caused inactivation of the JNK-mTORC1, NF-κB, and Wnt/β-catenin pathways in tumor cells. Induction of MyD88 knockout in the intestinal tumor-derived organoids, but not in the normal IEC-derived organoids, induced apoptosis and reduced their growth. Treatment with the MyD88 inhibitor ST2825 also suppressed the growth of the intestinal tumor-derived organoids. Knockdown of MYD88 in human CRC cell lines with mutations in APC or CTNNB1 induced apoptosis and reduced their proliferation as well. These results indicate that MyD88 loss is synthetic lethal with mutational activation of the Wnt/β-catenin signaling in intestinal tumor epithelial cells. Inhibition of MyD88 signaling can thus be a novel therapeutic strategy for familial adenomatous polyposis (FAP) as well as for colorectal cancer harboring mutations in the Wnt/β-catenin signaling.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is frequently activated in cancers and can be counteracted with the clinical mTORC1 inhibitors everolimus and temsirolimus. Although mTORC1 and dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. Using the cis-Apc/Smad4 mouse model of locally invasive intestinal adenocarcinoma, we show that administration of everolimus or the dual mTORC1/2 inhibitor AZD8055 significantly reduces the growth of intestinal tumors. In contrast, although everolimus treatment at earlier phase of tumor progression delayed invasion of the tumors, both inhibitors exhibited little effect on blocking invasion of the tumors when administered later in their progression. Biochemical and immunohistochemical analyses revealed that treatment of cis-Apc/Smad4 mice with everolimus or AZD8055 induced marked increases in epidermal growth factor receptor (EGFR) and MEK/ERK signaling in tumor epithelial and stromal cells, respectively. Notably, co-administration of AZD8055 and the EGFR inhibitor erlotinib or the MEK inhibitor trametinib was sufficient to suppress tumor invasion in cis-Apc/Smad4 mice. These data indicate that mTOR inhibitor resistance in invasive intestinal tumors involves feedback signaling from both cancer epithelial and stromal cells, highlighting the role of tumor microenvironment in drug resistance, and support that simultaneous inhibition of mTOR and EGFR or MEK may be more effective in treating colon cancer.

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of cell death in several cancer cells, but many cells are resistant to TRAIL. The mechanism that determines sensitivity to TRAIL-killing is still elusive. Here we report that deletion of TAK1 kinase greatly increased activation of caspase-3 and cell death after TRAIL stimulation in keratinocytes, fibroblasts and cancer cells. Although TAK1 kinase is involved in NF-kappaB pathway, ablation of NF-kappaB did not alter sensitivity to TRAIL. We found that TRAIL could induce accumulation of reactive oxygen species (ROS) when TAK1 was deleted. Furthermore, we found that TAK1 deletion induced TRAIL-dependent downregulation of cIAP, which enhanced activation of caspase-3. These results show that TAK1 deletion facilitates TRAIL-induced cell death by activating caspase through ROS and downregulation of cIAP. Thus, inhibition of TAK1 can be an effective approach to increase TRAIL sensitivity.