Aldolase - Metabolic Enzymes with Great Potentials for Cancer Theraputics

The metabolic network plays an important role in homeostasis, which is a nature’s way of keeping everything balanced inside our bodies. In recent years, it has been discovered that within cancerous cells, the metabolic network is somehow tweaked.

The research team led by Dr. Michael Hsiao of Genome Research Center has selected several related genes that have a high degree of performance in cancer cells and did large-scale high-throughput screening of metabolic enzyme to see if there are any con-nections. Over a pretty long period of time, they had published quite some results in various top-ranking journals. Obviously, they have drew attentions, and the team was invited by the top Metabolism review journal Trends in Endocrinology and Metabolism, a branch magazine of the Cells Press, to write up a summarized report.

Glycolysis plays an initial role of metabolic network and it takes a total of ten steps to convert glucose to pyruvate, which is then further transported to the mitochondria to carry out the citrate cycle and generate energy in the unit of adenosine triphosphate, aka. ATP. Interestingly, scientists have constantly found out some cancer cells prefer using lactate catalyzed from pyruvate, this is known as “the Warburg effect.” The Warburg effect not only transforms most of the pyruvate to lactate, but also regulates several in-termediates and precursor production for several metabolic synthesis pathways to the benefits of cancer cells. These detours include the pentose phosphate pathway, fatty acid synthesis, and amino acid synthesis…etc.

Aldolase, one of the glycolysis genes being watched by the Hsiao's team, has high ex-pression and positive correlation with the metastasis and recurrence status of lung cancer. Through in vitro and in vivo models, they have discovered that ALDOA could acceler-ate glycolysis turn over and promotes lactate production. Moreover, lactate acid inhibits the activity of prolyl hydroxylase (PHD) to prevent HIF-1alpha degradation. This result was published last September in Cancer Letters journal (Cancer Lett. 2017 Sep 10;403:28-36.).

 

They have also identified that the Aldolase family, including the subtypes ALDOA, ALDOB, and ALDOC have their own preferences and are expressed in different organs. The Hsiao’s team is the first one to have done a thorough and systematic check to clari-fy the similarities and differences among aldolase family types.

The first author of this review Dr. Chang Yu-Chan has pointed out that Aldolase family members have specificity and functional complementarity and are significantly corre-lated with several clinical parameters. It’s necessary to understand the signature of al-dolase family contributes to cancer and disease research and further translational medi-cine. He thinks their team has already paved the way for future investigations.

Dr. Yang Yi-Chieh believes that by organizing the complete functions of the aldolase including various isoforms in the human body, it will not only be helpful for cancer re-search, but also provide a new way for understanding and treatments of other diseases.

Dr. Tian Ji-Ping who is a physician in China Medical University Hospital said that “the non-enzyme functions of these genes are highly influential and specific to diseases and cancers, and they have the potential to serve as a clinical monitoring marker in the fu-ture.”

Another physician, Dr. Yang Chih-Jen of Kaohsiung Medical University affiliated Kaohsiung Municipal Ta-Tung Hospital pointed out that, “our previous lung cancer study had found that overexpression of aldolase A in non-small cell lung cancer could promote cancer metastasis, and correlated with poor survival rate in clinical patients whatever overall survival and disease-free survival. In addition, ALDOA regulated HIF1 a signaling activated and downstream factor MMP9 for lung metastasis. This axis can be used as a target for future development of new drugs.”

The team feels very honored by the Trends Endocrinol Metab Editor’s invitation to do a comprehensive review of aldolase related literatures. They hope the study of the en-zymes and non-enzymes of metabolism on cancers research will attract more attentions in cancer studies.

The full text of this review article can be read online: https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(18)30108-5

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