![]() ![]() Because HCT15-AA cells are less proliferative than their parental cells, they were injected into nude mice 10 days earlier than their parental cells. (c) Scheme for treatment paradigm of subcutaneous tumor xenografts. Right, percentages of apoptotic cells under the indicated conditions. RNAi efficiency was determined by Western blotting 48 h after transfection with siRNA. Left, knockdown of p65 in HCT15 and HCT116 cells. (b) Depletion of p65 compromised the survival of CRC-AA. Cultured cells were exposed to BAY11-7082 (0.1 μM) for 12 d to allow for colony formation. (a) Inhibition of colony formation by BAY11-7082 in CRC-AA and their parental cells. ![]() Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF- κB axis in cancer cells adapted to acidic microenvironment.ĬRC-AA cells are more sensitive to NF- κB inhibition or depletion. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF- κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF- κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF- κB axis. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF- κB inhibition or depletion, suggesting that NF- κB supports the survival of CRC-AA by maintaining redox homeostasis. NF- κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. We here show that NF- κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. ![]() Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. ![]()
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