Polyamine Regulation in Colon Cancer

Polyamines are vital for the growth and function of normal cells. The amino acid-derived polyamines like putrescine, spermidine and spermine that are the main polyamines found in prokaryotes and eukaryotes have long been associated with cell growth and cancer. Specific oncogenes and tumor suppressor genes regulate polyamine metabolism. Regulation of these polyamines is chiefly associated with cancers pertaining to the colon. Polyamines are formed by the enzymatic decarboxylation of amino acids like ornithine or arginine by ornithine decarboxylase-1 (ODC1), the enzyme required for the first stage in polyamine synthesis. ODC1 is subject to both positive and negative feedback regulation by polyamines: high polyamine concentrations decrease, and low polyamine concentrations increase, the activity of ODC1.Feedback regulation of ODC1 is a mixture of post-transcriptional regulation and the induction of a unique ODC1-specific inhibitor termed ornithine decarboxylase antizyme (OAZ). OAZ binds to ODC1 and the OAZ-ODC1 complex is degraded by the 26S proteasome. Unusually, the degradation of ODC1 by this proteasome occurs in an ATP-dependent, but ubiquitin-independent manner. ODC1 is released from OAZ by another unique protein, AZIN1, which liberates ODC1 in the presence of growth stimuli by virtue of having a higher affinity for OAZ than ODC1. Additionally, OAZ can alter polyamine homoeostasis by down-regulating polyamine uptake independent of its effects on ODC1. The expression of full length adenomatous polyposis coli (APC) results in up-regulation of OAZ. APC also increases expression of Mad1, which forms hetero complexes with the c-Myc binding partner, MAX. c-Myc acts as a transcriptional activator and Mad1 as the transcriptional repressor for ODC1 gene expression. Mad1 competes with c-Myc for binding to MAX, thereby decreasing the levels of c-Myc-MAX complexes. In addition, SSAT gene transcription is negatively regulated by the K-RAS oncogene through a mechanism involving PPAR-γ. PPAR-γ positively regulates the transcription of SSAT through the PPAR response element in the SSAT promoter. K-RAS suppresses SSAT transcription by inhibiting PPAR-γ expression and subsequently binding to the SSAT promoter. This maintains polyamine homeostasis and regulates polyamine efflux through DAX.In contrast, when wild type APC is lost in intestinal epithelia, during development of colon cancer, decreased OAZ activity contributes to increased ODC levels. Defects in the APC gene may occur in at least 90% of colon adenomas and cancers and are responsible for both inherited and sporadic forms of the cancer. This leads to CTNN-β/TCF4 association and translocation to the nucleus where transcription of target gene, c-Myc, is activated, leading to high levels of ODC and intracellular polyamine accumulation. Similarly, K-RAS, which is commonly mutated and aberrantly activated in human colon cancer and other gastrointestinal cancers, strongly inhibits PPAR-γ expression and subsequent binding to the SSAT promoter. This results in loss of polyamine efflux and facilitates neoplasia/invasion by cancer cells. So, polyamine synthesis and catabolism are both regulated by signaling pathways that are influenced by oncogenes and tumour suppressor genes. Aberrant APC and K-RAS expression essential for neoplasia indicate how polyamine levels become increased in colon and other gastrointestinal cancers.Reducing high polyamine levels in tissues during cancer development might require targeting two or more of these processes. Agents such as α-DFMO which inhibits ODC1 and activates PPAR-γ function are possible therapeutic approaches to treat colon cancers. (Upgraded 07/2021)