Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases

Abstract

Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.

Keywords: Apoptosis; Autophagy; Colon; Colorectal cancer; Inflammation; Therapy; c-MYC.

Figure 1

Schematic representation of the structure, regulation and main effects of c-MYC. A: The c-MYC protein consists of three domains: N-terminal, Central region, and C-terminal. The Central region and the C-terminal domain of c-MYC are responsible for protein-protein interactions that result in transcriptional repression by c-MYC. The C-terminal domain contains a basic (B) helix-loop-helix (HLH)-leucine zipper (LZ) motif that is necessary for interaction with different proteins (such as Max), and physiological recognition of DNA target sequences[7,58]; B: Developmental and mitogenic signals tightly regulate c-MYC gene expression both in normal (nontransformed) and in transformed cells via the MAPK/ERK pathway. MicroRNAs display a dual-faced role in the c-MYC regulatory network; both as regulators and as targets of c-MYC. The stability of the c-MYC protein also represents a particularly effective mechanism of gene regulation. c-Myc-S: Truncated c-Myc protein; MB1 and MB2: Evolutionarily conserved Myc Box sequences; NLS: Nuclear localization signal; Shh: Sonic hedgehog; EGF: Epidermal growth factor; MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase.

Figure 2

Schematic illustration of the relation of c-MYC to p53 following DNA damage in the intestine.

Figure 3

Interplay of AMBRA1, c-MYC and mTOR in colorectal cancer cells. AMBRA1 links autophagy to cell proliferation by facilitating c-MYC demolition. AMBRA1 promotes c-MYC phosphorilation and proteasomal degradation, therefore prevents hyperprolifearion and tumorigenesis. mTORC1 negatively controls the function of AMBRA1, thus finally supporting c-MYC-driven cell proliferation. Arrows represent stimulation or increase; blocked arrows represent inhibition; broken lines represent indirect effects. AMBRA1: Activating molecule in Beclin-1 regulated autophagy; mTORC1: Mammalian target of rapamycin complex 1; PP2A: Protein phosphatase 2A.