Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines in vitro and formation of metastatic lung cancer foci in vivo. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both in vitro and in vivo. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis.Significance: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non–small lung cancer and that blocking this interaction could be an effective cancer treatment.

Rationale: Metabolic alterations contribute to cancer development and progression. However, the molecular mechanisms relating metabolism to cancer metastasis remain largely unknown. Objectives: To identify a key metabolic enzyme that is aberrantly overexpressed in invasive lung cancer cells and to investigate its functional role and prognostic value in lung cancer. Methods: The differential expression of metabolic enzymes in noninvasive CL1-0 cells and invasive CL1-5 cells was analyzed by a gene expression microarray. The expression of target genes in clinical specimens from patients with lung cancer was examined by immunohistochemistry. Pharmacologic and gene knockdown/overexpression approaches were used to investigate the function of the target gene during invasion and metastasis in vitro and in vivo. The association between the target gene expression and clinicopathologic parameters was further analyzed. Bioinformatic analyses were used to discover the signaling pathways involved in target gene-regulated invasion and migration. Measurements and Main Results: Squalene synthase (SQS) was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among patients with lung cancer. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor receptor 1 in a cholesterol-dependent manner, which resulted in the enhancement of nuclear factor-κB activation leading to matrix metallopeptidase 1 up-regulation. Conclusions: Up-regulation of SQS promotes metastasis of lung cancer by enhancing tumor necrosis factor-α receptor 1 and nuclear factor-κB activation and matrix metallopeptidase 1 expression. Targeting SQS may have considerable potential as a novel therapeutic strategy to treat metastatic lung cancer.

Changes in cell growth and metabolism are affected by the surrounding environmental factors to adapt to the cell’s most appropriate growth model. However, abnormal cell metabolism is correlated with the occurrence of many diseases and is accompanied by changes in galectin (Gal) performance. Gals were found to be some of the master regulators of cell–cell interactions that reconstruct the microenvironment, and disordered expression of Gals is associated with multiple human metabolic-related diseases including cancer development. Cancer cells can interact with surrounding cells through Gals to create more suitable conditions that promote cancer cell aggressiveness. In this review, we organize the current understanding of Gals in a systematic way to dissect Gals’ effect on human disease, including how Gals’ dysregulated expression affects the tumor microenvironment’s metabolism and elucidating the mechanisms involved in Gal-mediated diseases. This information may shed light on a more precise understanding of how Gals regulate cell biology and facilitate the development of more effective therapeutic strategies for cancer treatment by targeting the Gal family.

Cholesterol is the major component of lipid rafts. Squalene synthase (SQS) is a cholesterol biosynthase that functions in cholesterol biosynthesis, modulates the formation of lipids rafts and promotes lung cancer metastasis. In this study, we investigated the lipid raft-associated pathway of SQS in lung cancer. Gene expression microarray data revealed the upregulation of secreted phosphoprotein 1 (SPP1; also known as osteopontin, OPN) in CL1-0/SQS-overexpressing cells. Knockdown of OPN in SQS-overexpressing cells inhibits their migration and invasion, whereas an OPN treatment rescues the migration and invasion of SQS knockdown cells. High OPN expression is associated with lymph node status, advanced stage and poor prognosis in patients with lung cancer. Moreover, patients with high SQS expression and high OPN expression show poor survival compared with patients with low SQS expression and low OPN expression. SQS induces the phosphorylation of Src and ERK1/2 via OPN, resulting in increased expression of MMP1 and subsequent metastasis of lung cancer cells. Based on our findings, SQS expression increases the expression of OPN and phosphorylation of Src through cholesterol synthesis to modulate the formation of lipid rafts. SQS may represent a therapeutic strategy for lung cancer.

Breast cancer is the most common female‐specific malignancy in Taiwan and developed countries worldwide, and its incidence continues to grow. 14‐3‐3ε (YWHAE), which belong to 14‐3‐3 family, it has been reported up‐regulated in breast cancer tissues. However, the clinical implication and function of YWHAE in breast cancer remains unclear. In this study, we investigated the prognostic value of the YWHAE in human breast cancer. Immunohistochemistry was used to analyze YWHAE expression in breast cancer tissues. Cell model was applied to examine the functions of YWHAE. The chemotherapeutic agents were used to evaluate the effect of YWHAE in breast cancer cell lines. YWHAE expression was associated with tumor size, lymph node metastasis, and poor patient survival in patients with breast cancer. YWHAE overexpression significantly increased the proliferation, migration, and invasion abilities of breast cancer cells. Knockdown of YWHAE expression reduced the expression of Snail and Twist in breast cancer cells. We also found that YWHAE was responsible for the resistance of breast cancer cells to chemotherapeutic agents, and knockdown of YWHAE enhanced sensitivity to multiple chemotherapeutic agents in breast cancer cells. Taken together, our findings indicated that YWHAE promoted cancer progression and chemoresistance in breast cancer cells and can be a potential therapeutic target for breast cancer.