PETCM

PETCM is an activator of caspase-3 [1].

Caspase-3 is a member of the cysteine-aspartic acid protease family and interacts with caspase-8 and caspase-9. Sequential activation of caspases plays an important role in cell apoptosis.

In HeLa S-100 cell cytosol, PETCM activated caspase-3 in a dose-dependent way and induced apoptosome formation. PETCM (0.2 mM) caused Apaf-1 shifted to a size of ~1 million daltons, which indicating apoptosome formation. Also, PETCM function required dATP. The activation effect of PETCM on caspase-3 was independent of PHAP proteins. When inhibited the activation activity of the PHAP proteins, PETCM reversed the suppression. When added to Q30 (Apaf-1/procaspase-9) plus cytochrome c and 10 μM dATP, recombinant PHAPI activated caspase-3. The activity was inhibited by recombinant ProT. While, PETCM reversed the inhibitory effect of ProT. PHAPI didn’t affect apoptosome formation and activated caspase-9 and Apaf-1, which were associated with apoptosome. ProT efficiently blocked formation of apoptosome and PETCM relieved this effect [1].

Reference:
[1].  Jiang X, Kim HE, Shu H, et al. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science, 2003, 299(5604): 223-226.

Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway.[Pubmed:12522243]

Science. 2003 Jan 10;299(5604):223-6.

A small molecule, alpha-(trichloromethyl)-4-pyridineethanol (PETCM), was identified by high-throughput screening as an activator of caspase-3 in extracts of a panel of cancer cells. PETCM was used in combination with biochemical fractionation to identify a pathway that regulates mitochondria-initiated caspase activation. This pathway consists of tumor suppressor putative HLA-DR-associated proteins (PHAP) and oncoprotein prothymosin-alpha (ProT). PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. PETCM relieved ProT inhibition and allowed apoptosome formation at a physiological concentration of deoxyadenosine triphosphate. Elimination of ProT expression by RNA interference sensitized cells to ultraviolet irradiation-induced apoptosis and negated the requirement of PETCM for caspase activation. Thus, this chemical-biological combinatory approach has revealed the regulatory roles of oncoprotein ProT and tumor suppressor PHAP in apoptosis.

Direct activation of the apoptosis machinery as a mechanism to target cancer cells.[Pubmed:12808146]

Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7533-8.

Apoptosis plays a pivotal role in the cytotoxic activity of most chemotherapeutic drugs, and defects in this pathway provide a basis for drug resistance in many cancers. Thus the ability to restore apoptosis by using small molecules could have important therapeutic implications. Using a cell-free assay to simultaneously target multiple components of the apoptosis pathway, we identified a class of compounds that activate caspases in a cytochrome c-dependent manner and induce apoptosis in whole cells. By reconstituting the apoptosis pathway with purified proteins, we determined that these compounds promote the protein-protein association of Apaf-1 into the functional apoptosome. These compounds exert cytostatic and cytotoxic effects on a variety of cancer cell lines while having little or no activity against the normal cell lines tested. These findings suggest that direct activation of the basic apoptosis machinery may be a viable mechanism to selectively target cancer.

PETCM is an activator of caspase-3 and acts as an cytochrome c (cyto c)-dependent manner. PETCM promotes Apaf-1 oligomerization and induces cell apoptosis in HeLa cells.

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