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Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2.

Voutsadakis IA - J. Cell. Mol. Med. (2007 Mar-Apr)

Bottom Line: UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma.Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population.NSAIDs have also Cox-independent anti-proliferative effects.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, University Hospital of Larissa, Larissa 41110, Greece. ivoutsadakis@yahoo.com

ABSTRACT
Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.

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TGFβ signalling and interactions with K-ras.
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fig05: TGFβ signalling and interactions with K-ras.

Mentions: Ligation of TGF-β to its cell surface receptor complex TβRII and TβRI initiates a signal transduction path-way by activating the proteins Smad2 and Smad3 (R-Smads), which in conjunction with the co-activator Smad4 (also known as DPC4–deleted in pancreatic carcinoma 4) co-operate with other transcription factors for the transcription of target genes. Smad6 and Smad7 are inhibitory type Smads that inhibit R-Smad mediated transcription (Fig. 5). Seven different TβRIs and five TβRIIs exist in vertebrate cells and may associate with each other in multiple combinations [66]. Activation of the TβRII and TβRI receptors facilitates additionally an interaction with PI3-K leading to akt activation. Moreover, TβRII/TβRI stimulates phosphatase PP2A, an inhibitor of the kinase p70S6K. Ras may also be activated by TRs either directly or through PI3-K activation [67].


Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2.

Voutsadakis IA - J. Cell. Mol. Med. (2007 Mar-Apr)

TGFβ signalling and interactions with K-ras.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822826&req=5

fig05: TGFβ signalling and interactions with K-ras.
Mentions: Ligation of TGF-β to its cell surface receptor complex TβRII and TβRI initiates a signal transduction path-way by activating the proteins Smad2 and Smad3 (R-Smads), which in conjunction with the co-activator Smad4 (also known as DPC4–deleted in pancreatic carcinoma 4) co-operate with other transcription factors for the transcription of target genes. Smad6 and Smad7 are inhibitory type Smads that inhibit R-Smad mediated transcription (Fig. 5). Seven different TβRIs and five TβRIIs exist in vertebrate cells and may associate with each other in multiple combinations [66]. Activation of the TβRII and TβRI receptors facilitates additionally an interaction with PI3-K leading to akt activation. Moreover, TβRII/TβRI stimulates phosphatase PP2A, an inhibitor of the kinase p70S6K. Ras may also be activated by TRs either directly or through PI3-K activation [67].

Bottom Line: UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma.Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population.NSAIDs have also Cox-independent anti-proliferative effects.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, University Hospital of Larissa, Larissa 41110, Greece. ivoutsadakis@yahoo.com

ABSTRACT
Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.

Show MeSH
Related in: MedlinePlus