Cancer and Epigenetic Reversion—The Fundamental Role of Redox

To the Editor-in-Chief:

It is unfortunate that Maniotis and associates1 did not refer to our work,2,3 which predicts and explains their findings and may have stimulated American Journal of Pathology readers to design novel experiments. Maniotis et al,1 like Puck et al,4 showed that in cancer cells, chromatin is abnormally condensed. Puck et al4 also showed that the cancer cell surfaces are studded with oscillating knobs and are associated with aggregated actin-containing deposits near the membrane. Both groups showed that cAMP and other agents can reverse the above phenotypic characteristics of malignant cells and concluded that the cytoskeleton carries information from the cell surface and the cellular environment, which determines chromatin organization and gene regulation (mechanogenomics). According to Maniotis et al,1 “elucidating the mechanism through which extracellular matrix components influence tumor cell and DNA organization may lead to the identification of new potential targets for cancer therapy.”

Such a mechanism was proposed by one of us (E.P.-E.) in a redox theory of cellular function and structure.2 Points relating to neoplasia are described as follows.

1. The cell is a dynamic entity with superimposed oscillations characterized by anisotropic, temporal-spatial fluctuations. The energy sources are protein sulfhydryl groups (SHs) and ATP.

2. Cellular structure, function, and differentiation are determined by the cellular redox (and the associated phosphorylation), its temporal-spatial distribution, and its oscillations. The redox of the actin/myosin system and charge transfer between myosin and actin play a critical role.

3. The main determinants of the cellular redox are the SHs of the acid-soluble proteins.

4. Carcinogens cause oxidation of the extracellular matrix and cells and, thus, changes in the redox oscillations. Cancer cells show similar redox levels and similar anisotropic redox distribution and oscillations; because of these attributes, they have several common characteristics, such as chromatin condensation, oscillating knobs, invasion/metastasis, and aneuploidy.

5. Cancer can be treated by i) oxidizing agents, by which cancer cells are destroyed, but the noncancerous tissue remains oxidized and thus prone to future malignant transformation, and ii) agents that reduce the disulfide bonds of the acid-soluble proteins, which will revert both cells and environment to normal or destroy the cancer cells.

There is evidence that supports the predictions of the redox theory of cancer. All carcinogens oxidize the fast-reacting SH groups. Compared with normal tissue, the tissue of cancer patients—and in particular neoplastic cells—are more oxidized2 (A. Maniotis, personal communication). Oxidizing agents induce “changes in morphology [loss of actin and microtubular organization and the appearance of blebs (knobs)], cytoskeleton and cell-cell coupling,” which are reversed by reducing agents.5

Our experimental evidence shows that redox plays a key role in contraction/relaxation (condensation/decondensation) oxidation leading to contraction and reduction to relaxation.3 Data also exist that “demonstrate a definite periodicity in the initiation of transcription”6; “translation is completely coupled with transcription7”; “thiol disulphide transformation constitutes one of the mechanisms, which control the functional status of individual proteins important for gene expression.”8

According to Maniotis et al,1 cAMP acts through the cAMP-dependent protein kinase A, which in turn is thought to play a critical role in regulating transition through the cell cycle. The protein kinase A activity is redox-dependent.9 However, as Paul Nurse10 pointed out, the molecular approaches to cell-cycle control “retreat into an infinite regress of regulators of regulators.”

For more than half a century, evidence existed for a cyclic variation of SH groups during the cell cycle. They were thought to be those of glutathione and to be the regulator of the cell cycle. More recently, it has been shown that the SHs are those of the acid-soluble proteins (eg, myosin).2 In other words, the cell cycle is regulated by the cyclic oscillations of the redox.