Figure 1.

Molecular events involved in hypoxia-induced endosome acidification and chemoresistance. Normoxic cancer cells have organellar pH and a slightly acidic cytophasmic pH. In these cells, weak-base chemotherapeutics, such as doxorubicin, are not efficiently sequestracted and the drugs can efficiently reach their cellular target leading to cell death. In hypoxic cancer cells, the acidification of the endosomal compartments leads to exacerbation of the vesicular pH gradient and drug trapping. Hypoxia-induced acidification of endosomal PH is due to mislocalization of the sodium/ hydrogen exchanger 6 (NHE6) because of its enhanced binding to receptor of activated protenin C kinase 1 (RACK1) throught a PKC-dependent mechanism.