Summary
Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumourigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programs by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anti-cancer metabolism therapy development in future.
The Serine-Glycine-One-Carbon (SGOC) pathway is pivotal in multiple anabolic processes. Expression levels of SGOC genes are deregulated under tumorigenic conditions, suggesting participation of oncogenes in deregulating the SGOC biosynthetic pathway. However, the underlying mechanism remains elusive. Here, we identified that Interleukin enhancer-binding factor 3 (ILF3) is overexpressed in primary CRC patient specimens and correlates with poor prognosis. ILF3 is critical in regulating the SGOC pathway by directly regulating the mRNA stability of SGOC genes, thereby increasing SGOC genes expression and facilitating tumor growth. Mechanistic studies showed that the EGF-MEK-ERK pathway mediates ILF3 phosphorylation, which hinders E3 ligase speckle-type POZ protein (SPOP)-mediated poly-ubiquitination and degradation of ILF3. Significantly, combination of SGOC inhibitor and the anti-EGFR monoclonal antibody cetuximab can hinder the growth of patient-derived xenografts that sustain high ERK-ILF3 levels. Taken together, deregulation of ILF3 via the EGF-ERK signaling plays an important role in systemic serine metabolic reprogramming and confers a predilection toward CRC development. Our findings indicate that clinical evaluation of SGOC inhibitor is warranted for CRC patients with ILF3 overexpression.
Colon cancer is one
of the most common cancers with high mortality
in humans. Early diagnosis and treatment of colon cancer is of great
significance for cancer therapy. Numerous theranostic agents have
been developed to detect and kill cancer cells. However, few reports
have focused on how these agents control and affect the gene expression
of cancer cells in vivo. Herein, three pyridinium-functionalized tetraphenylethylene
derivatives, namely, TPE-OM, TPE-H, and TPE-NO2, with electron-donating
and electron-withdrawing groups were facilely synthesized as theranostic
agents for cell imaging and anticolon cancer therapy. Among these
AIE luminogens (AIEgens), TPE-OM with donor and acceptor structure
showed the best treatment efficacy for colon cancer through systematic
biological evaluation and comparison. Both in vitro cell imaging and
in vivo tumor treatment experiments demonstrated that TPE-OM can be
utilized as an efficient theranostic agent to diagnose and kill colon
cancer cells. Flow cytometric analysis revealed that the cell cycle
process was disturbed by TPE-OM in colon cancer cells. Deep insight
into the gene level revealed that the expressions of cell-cycle-promoting
genes was inhibited upon addition of TPE-OM. This study may open a
new venue for unraveling the mechanisms of cancer metastasis.
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