Intestinal epithelial cancer cell anoikis resistance: EGFR‐mediated sustained activation of Src overrides Fak‐dependent signaling to MEK/Erk and/or PI3‐K/Akt‐1

Abstract

Herein, we investigated the survival roles of Fak, Src, MEK/Erk, and PI3-K/Akt-1 in intestinal epithelial cancer cells (HCT116, HT29, and T84), in comparison to undifferentiated and differentiated intestinal epithelial cells (IECs). We report that: (1) cancer cells display striking anoikis resistance, as opposed to undifferentiated/differentiated IECs; (2) under anoikis conditions and consequent Fak down-activation, cancer cells nevertheless exhibit sustained Fak-Src interactions and Src/MEK/Erk activation, unlike undifferentiated/differentiated IECs; however, HCT116 and HT29 cells exhibit a PI3-K/Akt-1 down-activation, as undifferentiated/differentiated IECs, whereas T84 cells do not; (3) cancer cells require MEK/Erk for survival, as differentiated (but not undifferentiated) IECs; however, T84 cells do not require Fak and HCT116 cells do not require PI3-K/Akt-1, in contrast to the other cells studied; (4) Src acts as a cornerstone in Fak-mediated signaling to MEK/Erk and PI3-K/Akt-1 in T84 cells, as in undifferentiated IECs, whereas PI3-K/Akt-1 is Src-independent in HCT116, HT29 cells, as in differentiated IECs; and (5) EGFR activity inhibition abrogates anoikis resistance in cancer cells through a loss of Fak-Src interactions and down-activation of Src/MEK/Erk (T84, HCT116, HT29 cells) and PI3-K/Akt-1 (T84 cells). Hence, despite distinctions in signaling behavior not necessarily related to undifferentiated or differentiated IECs, intestinal epithelial cancer cells commonly display an EGFR-mediated sustained activation of Src under anoikis conditions. Furthermore, such sustained Src activation confers anoikis resistance at least in part through a consequent sustenance of Fak-Src interactions and MEK/Erk activation, thus not only overriding Fak-mediated signaling to MEK/Erk and/or PI3-K/Akt-1, but also the requirement of Fak and/or PI3-K/Akt-1 for survival.

Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells

“…5). Interestingly, TGF-␣-mediated autocrine activation in FOLFOX-resistant HCT-116 cells was less affected by Slfn-3 than in FOLFOX-resistant HT-29 cells, consistent with their aggressive characteristics compared with FOLFOX-resistant HT-29 cells (6,10). This finding is consistent with our observation that Slfn-3 transfection inhibits tumorosphere/colonosphere formation potential of both FOLFOX-resistant HCT-116 and HT-29 cells, which suggests that Slfn-3 may stimulate differentiation and inhibit ABCG2 activity and tumorosphere/ colonosphere formation of colon cancer stemlike cells.…”

Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

“…Although total levels of Akt/protein kinase B and phosphorylation of Bad Ser112 were unchanged, Akt/ PKC and ERK phosphorylation were moderately increased after application of inhibitors (Fig. 7A, bottom), suggesting that in ovarian cancer cells, similar to breast and intestinal epithelial cancer, PI3K and MAPK pathways are affected by EGFR downstream signaling evens (54,55).…”

The Role Integrins in Invasii and Metastatic Skin of Malignant Tumors

“…блуждать), гибель клетки при потере контакта с окружающим внеклеточным матриксом. Изменение и блокирование данного механизма ассоцииру-ется с развитием метастазирования [12].…”

“…Множество проведенных исследований по изучению зако-номерностей роста и прогрессии опухолей кожи показа-ли, что чем выше содержание интегринов в опухоли, тем выше скорость ее инвазии и более выраженный ангиогенез [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Суть этих исследований заключалась в сравнении количества интегринов на разных клонах одной и той же опухоли, с определением скорости роста, инвазии и мета-стазирования каждого из клонов с последующим сравне-нием их между собой.…”

“…Суть этих исследований заключалась в сравнении количества интегринов на разных клонах одной и той же опухоли, с определением скорости роста, инвазии и мета-стазирования каждого из клонов с последующим сравне-нием их между собой. Результаты всех исследований были схожими: клоны, имевшие самый быстрый и злокаче-ственный рост, показывали наибольшую экспрессию ин-тегринов по сравнению с менее агрессивными вариантами тех же опухолей [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”