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Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects.

Mizejewski GJ - Cancers (Basel) (2011)

Bottom Line: Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation.The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF).As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

View Article: PubMed Central - PubMed

ABSTRACT
The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides against nine different human cancer types. Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation. The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF). The overall mechanisms of action of both peptides are discussed in light of their differing modes of cell attachment and uptake fortified by RNA microarray analysis and electrophysiologic measurements of cell membrane conductance and resistance. As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

No MeSH data available.


Related in: MedlinePlus

(A). A three-dimensional v-shaped helix/ribbon computer model of human alpha-fetoprotein (HAFP) is displayed. GIP-34 amino acid buried segment (D) is shown in the black boxed configuration. Minimal energy computer model of GIP-34 and GIP-8 and their amino acid sequences are displayed above the v-shaped HAFP model (B and C).
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f1-cancers-03-02709: (A). A three-dimensional v-shaped helix/ribbon computer model of human alpha-fetoprotein (HAFP) is displayed. GIP-34 amino acid buried segment (D) is shown in the black boxed configuration. Minimal energy computer model of GIP-34 and GIP-8 and their amino acid sequences are displayed above the v-shaped HAFP model (B and C).

Mentions: Human alpha-fetoprotein (HAFP) is tumor-associated fetal protein, termed an oncofetal protein, consisting of 609 amino acids (AAs) including a 19 amino acid (AA) signal sequence [1-3]. HAFP has been shown to be a growth enhancing factor in its circulating, compact-folded, native full length configuration in studies of both fetal and tumor cell growth and proliferation studies (Figure 1A) [4-6]. Having served as a serum biomarker for cancers of the liver, gonads, and gastrointestinal tract, HAFP is now being investigated as an activator of cell surface receptors as well as a regulator of cytoplasmic transcription factors involved in signaling pathways [7-9]. When present in stress and shock environments, full-length HAFP undergoes a conformational change which temporarily converts the growth enhancing oncofetal protein to a growth inhibitory form referred to as “transformed AFP” (tAFP) [10,11]. The peptide sequence of the transforming site on AFP has been identified and found to be composed of a 34-AA portion of the HAFP molecule, which serves as a growth inhibitory segment (Figure 1) [12]. This 34-AA stretch has been synthesized as a free peptide fragment and termed the “Growth Inhibitory Peptide” (GIP); it has since undergone extensive biological and biochemical characterization [12-15].


Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects.

Mizejewski GJ - Cancers (Basel) (2011)

(A). A three-dimensional v-shaped helix/ribbon computer model of human alpha-fetoprotein (HAFP) is displayed. GIP-34 amino acid buried segment (D) is shown in the black boxed configuration. Minimal energy computer model of GIP-34 and GIP-8 and their amino acid sequences are displayed above the v-shaped HAFP model (B and C).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757439&req=5

f1-cancers-03-02709: (A). A three-dimensional v-shaped helix/ribbon computer model of human alpha-fetoprotein (HAFP) is displayed. GIP-34 amino acid buried segment (D) is shown in the black boxed configuration. Minimal energy computer model of GIP-34 and GIP-8 and their amino acid sequences are displayed above the v-shaped HAFP model (B and C).
Mentions: Human alpha-fetoprotein (HAFP) is tumor-associated fetal protein, termed an oncofetal protein, consisting of 609 amino acids (AAs) including a 19 amino acid (AA) signal sequence [1-3]. HAFP has been shown to be a growth enhancing factor in its circulating, compact-folded, native full length configuration in studies of both fetal and tumor cell growth and proliferation studies (Figure 1A) [4-6]. Having served as a serum biomarker for cancers of the liver, gonads, and gastrointestinal tract, HAFP is now being investigated as an activator of cell surface receptors as well as a regulator of cytoplasmic transcription factors involved in signaling pathways [7-9]. When present in stress and shock environments, full-length HAFP undergoes a conformational change which temporarily converts the growth enhancing oncofetal protein to a growth inhibitory form referred to as “transformed AFP” (tAFP) [10,11]. The peptide sequence of the transforming site on AFP has been identified and found to be composed of a 34-AA portion of the HAFP molecule, which serves as a growth inhibitory segment (Figure 1) [12]. This 34-AA stretch has been synthesized as a free peptide fragment and termed the “Growth Inhibitory Peptide” (GIP); it has since undergone extensive biological and biochemical characterization [12-15].

Bottom Line: Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation.The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF).As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

View Article: PubMed Central - PubMed

ABSTRACT
The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides against nine different human cancer types. Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation. The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF). The overall mechanisms of action of both peptides are discussed in light of their differing modes of cell attachment and uptake fortified by RNA microarray analysis and electrophysiologic measurements of cell membrane conductance and resistance. As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

No MeSH data available.


Related in: MedlinePlus