Ripening-induced chemical modifications of papaya pectin inhibit cancer cell proliferation

Abstract

Papaya (Carica papaya L.) is a fleshy fruit with a rapid pulp softening during ripening. Ripening events are accompanied by gradual depolymerization of pectic polysaccharides, including homogalacturonans, rhamnogalacturonans, arabinogalactans, and their modified forms. During intermediate phases of papaya ripening, partial depolymerization of pectin to small size with decreased branching had enhanced pectin anti-cancer properties. These properties were lost with continued decomposition at later phases of ripening. Pectin extracted from intermediate phases of papaya ripening markedly decreased cell viability, induced necroptosis, and delayed culture wound closing in three types of immortalized cancer cell lines. The possible explanation for these observations is that papaya pectins extracted from the third day after harvesting have disrupted interaction between cancer cells and the extracellular matrix proteins, enhancing cell detachment and promoting apoptosis/necroptosis. The anticancer activity of papaya pectin is dependent on the presence and the branch of arabinogalactan type II (AGII) structure. These are first reports of AGII in papaya pulp and the first reports of an in vitro biological activity of papaya pectins that were modified by natural action of ripening-induced pectinolytic enzymes. Identification of the specific pectin branching structures presents a biological route to enhancing anti-cancer properties in papaya and other climacteric fruits.

Pectin Interaction with Immune Receptors is Modulated by Ripening Process in Papayas

“…The same tendency was found in both the Gal:Rha and Ara:Rha ratios, which could mean the loss of galactans and arabinogalactans side chain of rhamnogalacturonan type 1 (RG-I), which has Gal and/or Ara ramifications linked by the Rha. Taken together, these results with the ones from our previous study, in which papaya WSF was characterized at different ripening time points 18 , there is an increment of RG-I in WSF as papayas ripe. Besides, Ara and Gal amount decreased during ripening, while Rha increased, suggesting the presence of smaller chains of more highly branched RG-I, which is also in accordance with our previous study 18 .…”

“…The differences in these two bands over the papaya ripeness time points represent the changes in the methyl esterification profile, with an increment of DM and an increment of uronic acids. Using the 1740 cm −1 and 1600-1630 cm −1 bands it is possible to calculate the DM throughout the standard curve of DM values of commercially available pectin, as described elsewhere 18 . The results obtained follow the same tendency of DM increase for the WSF extracted from ripening papayas (Un-1-WSF: DM 38.1 ± 1.4; Un-2-WSF: DM 33.4 ± 0.2; I-WSF: DM 35.3 ± 0.9; R-1-WSF: DM 52.1 ± 2.1; R-2-WSF: DM 48.0 ± 1.2).…”

“…PG is the main enzyme over-expressed in papaya ripening and is responsible for pulp softening 17,19 . The PG action modifies the pectin structures and releases them into the WSF of the fruit pulp resulting in a shift from long galacturonan chains to medium chains 17,18 . The interaction of HG segments derived from pectic polysaccharides with PRR and its health effects have been described elsewhere 25 .…”

“…These enzymes are responsible for the cell wall disassembling with concomitant changes in papaya DF structure, for instance, through the generation during ripening of water-soluble fractions rich in pectin with low molecular weight 17 . The papaya water-soluble fraction (WSF) isolated from the fruit pulp is mostly composed of pectin (~95%) but has different structural features depending on the papaya ripening stage 18 . These different pectin structures may have different host effects by differential modulation of PRR signaling 6,12 .…”

Structural-dependent effects of dietary fibers in colon cancer: Focus on dietary fiber naturally changed by the papaya ripening

“…The distinct effects of NDC from ripe and unripe papaya on NLR activation seem to be related to changes in the structure of NDC that occur during fruit ripening, as ripe papaya had increased proportion of homogalacturonans with higher degree of methylation compared to NDC from unripe papaya [121]. Notably, a similar NDC-also from papaya fruitinhibited CRC cells proliferation in vitro [149]. Furthermore, linear β-(1,2)-linked fructose oligosaccharides (inulin) from chicory root also activate NOD2 in HEK 293 hNOD2 reporter cells [115].…”