Studies on Cancer Chemoprevention by Traditional Folk Medicines XXV.—Inhibitory Effect of Isoliquiritigenin on Azoxymethane-Induced Murine Colon Aberrant Crypt Focus Formation and Carcinogenesis

ABSTRACT RhoA is involved in multiple cellular processes, including cytoskeletal organization, gene expression, and transformation. These processes are mediated by a variety of downstream effector proteins. However, which effectors are involved in cellular transformation and how these proteins are activated following interaction with Rho remains to be established. A unique feature that distinguishes the Rho family from other Ras-related GTPases is the insert region, which may confer Rho-specific signaling events. Here we report that deletion of the insert region does not result in impaired effector binding. Instead, this insert deletion mutant (RhoΔRas, in which the insert helix has been replaced with loop 8 of Ras) acted in a dominant inhibitory fashion to block RhoA-induced transformation. Since RhoΔRas failed to promote stress fiber formation, we examined the ability of this mutant to bind to and subsequently activate Rho kinase. Surprisingly, RhoΔRas-GTP coprecipitated with Rho kinase but failed to activate it in vivo. These data suggested that the insert domain is not required for Rho kinase binding but plays a role in its activation. The constitutively active catalytic domain of Rho kinase did not promote focus formation alone or in the presence of Raf(340D) but cooperated with RhoΔRas to induce cellular transformation. This suggests that Rho kinase needs to cooperate with additional Rho effectors to promote transformation. Further, the Rho kinase catalytic domain reversed the inhibitory effect of RhoΔRas on Rho-induced transformation, suggesting that one of the downstream targets of Rho-induced transformation abrogated by RhoΔRas is indeed Rho kinase. In conclusion, we have demonstrated that the insert region of RhoA is required for Rho kinase activation but not for binding and that this kinase activity is required to induce morphologic transformation of NIH 3T3 cells.

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Inhibitory Potential of Dietary Nutraceuticals on Cellular PI3K/Akt Signaling: Implications in Cancer Prevention and Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210716152224 ◽

2021 ◽

Vol 21 ◽

Author(s):

Arunaksharan Narayanankutty

Keyword(s):

Natural Products ◽

Cancer Prevention ◽

Cancer Progression ◽

Anticancer Agents ◽

Dietary Intervention ◽

Phosphatidyl Inositol ◽

Cancer Chemoprevention ◽

Inhibitory Effect ◽

Pi3k Pathway ◽

Mtor Pathway

Background: : The phosphatidyl inositol-3 kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling have been associated with many cellular physiological events such as proliferation, maturation, survival, and metabolism. Besides their roles in normal cells, the pathway is often upregulated in various cancers. Due to their prominent roles in the cancer progression events, it is now being considered a target for cancer therapy and cancer chemoprevention. Objectives: : The present review provides a concise outline of the role of the PI3K/Akt/mTOR pathway in carcinogenesis and progression events, including metastasis, drug resistance, and stemness. Further, emphasis is given to the PI3K/Akt/mTOR pathway inhibitory potentials of various food-derived bioactive components in cancer prevention. Methods: : Data on the PI3K/Akt/mTOR inhibiting natural products and their bioactive compounds have been obtained from PubMed/Medline, Scopus, Eurekaselect, etc. Findings from the above citation databases from 2000-2021 are included in the manuscript. Results:: Numerous compounds from plants have been isolated and identified as anticancer agents; among these, a predominant class is nutraceuticals. The PI3K pathway is the principal target of these natural products, and many of these drug candidates are under various stages of drug development. These compounds have shown a significant inhibitory effect on the kinase activities of PI3K and Akt, resulting in the abrogation of cancer initiation and progression events. In addition, these compounds have been shown to reverse the resistance to chemotherapeutic drugs and reduce the population of cancer stem cells. Conclusion: : The nutraceuticals are promising candidates as anticancer agents by blocking PI3K signaling cascades. As the PI3K is a central pathway to various receptor signaling, the dietary intervention may prove highly effective.

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