DOWNREGULATION OF KLF6 TUMOR SUPPRESSOR IN CANCER CELLS EXPRESSING MUTATED RASRAS AS ONCOGENIC DRIVER INCREASE THEIR VULNERABILITY TO CHEMOTHERAPY BASED ON ROCK INHIBITION

CASTELLARO, ANDRÉS; OCHOA, DENISE; ZALAZAR VILLARREAL, ROCÍO; BOCCO, JOSE LUIS

Mendoza

Congreso; SAIB Meeting 2022; 2022

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Early induction of KLF6 tumor suppressor following mitogenic stimulation mediated by growth factors and/or oncogene activation works as negative feedback to attenuate the extent of growth-promoting signaling. This function is characterized by a cell cycle arrest mediated by KLF6 which contributes to a decrease in both, cell proliferation and oncogenesis triggered by activated Ras, functions compatible with a tumor suppressor. However, during the cell cycle arrest imposed by KLF6, cells are more resistant to cell death mediated by chemotherapy drugs based on DNA damage agents or on mitotic stress, suggesting that alleviation of the early KLF6 induction would be required for efficient toxicity of this type of chemotherapy drugs. Accordingly, KLF6 silencing in cancer cells expressing mutated Ras as oncogenic driver (HCT116), increases the susceptibility to fasudil, a chemotherapy drug for cancer treatment based on inhibition of the Rho-associated protein kinases (ROCK1/2), enzymes playing a key role in cytokinesis and cancer progression. Additionally, KLF6 silencing per se leads to the accumulation of DNA damage, increased p53 expression, and signs of genomic instability. Hence our hypothesis is that KLF6 downregulation following its early induction will enhance cell vulnerability upon cell treatment with fasudil. More importantly, tumor cells expressing mutated Ras as oncogenic driver should be more susceptible than normal cells due to the proliferation stress, enhanced glycolisis and overload of the DNA repair system imposed by the mutated Ras signaling.Here we show that high doses of Vitamin C, in addition to produce oxidative stress, is able to downregulate KLF6 protein expression, increasing the vulnerability of HCT116 cancer cells to fasudil. These results suggest that the combined treatment with Vitamin C and fasudil could lead to increased toxicity of cells expressing mutated Ras, which is accompanied by a decrease in KLF6 protein level. Given no efficient therapy targeting mutated Ras has been successful to date, due to its non-pharmaceutical target status, these results open possibilities for the design of new therapeutic strategies, based on the downregulation of a tumor suppressor, such as KLF6, along with ROCK inhibition.