The Prime and Integral Cause of Cancer in the Post-Warburg Era

Abstract

Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as "the Warburg effect". In his early studies, Warburg looked at the effects of hydrogen ions (H⁺), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO₂ led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: "Special attention should be drawn to the remarkable influence of the bicarbonate…". Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new "pH-related paradigm of cancer", while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.

Keywords: Warburg effect nowadays; changing hallmarks in cancer; historical mishaps in metabolic cancer research; integrations among orthodox and heterodox oncology; pH in cancer primal etiology; pH-related therapeutic implications.

Figure 1

pH-related interplay among the most significant membrane-bound transporters, cellular alkalization, aerobic glycolysis and the Warburg effect. Cell alkalization, as induced by multiple previous upstream processes (see Table 2) is the primal and integral mediator of malignant transformation and the main metabolic and acid-base homeostatic derangement and anti-apoptotic factor, which is also fundamental in MDR. The secondary interstitial (TME) acidification of tumors originates the cancer proton reversal (CPR). Finally, this concatenation of pathological energetic changes drives the cascade of cancer progression and the metastatic process. Abbreviations: NHE1, Na⁺/H⁺ antiporter isoform 1; ASIC1, acid-sensing ion channel type 1a; Hv1, voltage-gated Na+ and H+ channel isoform 1; PTs, proton transporters; PPs, proton pumps; CPR, cancer proton reversal; MDR, multiple drug resistance; LA, lactic acid. For further details, see the text.