Gibberellic Acid Initiates ER Stress and Activation of Differentiation in Cultured Human Immortalized Keratinocytes HaCaT and Epidermoid Carcinoma Cells A431.

Mariya Vildanova,Elena Smirnova,Aleena Saidova,Polina Vishnyakova,Victoria Konduktorova,Galina Onishchenko

doi:10.3390/pharmaceutics13111813

Abstract

Diterpenoid plant hormone gibberellic acid (GA) plays an important role in regulation of plant growth and development and is commonly used in agriculture for activation of plant growth and food production. It is known that many plant-derived compounds have miscellaneous biological effects on animals and humans, influencing specific cellular functions and metabolic pathways. However, the effect of GA on animal and human cells remains controversial. We investigated the effect of GA on cultured human cell lines of epidermoid origin—immortalized non-tumorigenic keratinocytes HaCaT and carcinoma A431 cells. We found that at a non-toxic dose, GA upregulated the expression of genes associated with the ER stress response—CHOP, sXBP1, GRP87 in both cell lines, and ATF4 predominantly in A431 cells. We also showed that GA was more effective in upregulating the production of ER stress marker GRP78, autophagy marker LC3B-II, and differentiation markers involucrin and filaggrin in A431 cells than in HaCaT. We conclude that GA induces mild ER stress in both cell lines, followed by the activation of differentiation via upregulation of autophagy. However, in comparison with immortalized keratinocytes HaCaT, GA is more effective in inducing differentiation of carcinoma A431 cells, probably due to the inherently lower differentiation status of A431 cells. The activation of differentiation in poorly differentiated and highly malignant A431 cells by GA may lower the level of malignancy of these cells and decrease their tumorigenic potential.

Highlights

Plant hormones are biologically active substances of low molecular weight and diverse chemical composition
We found that gibberellic acid (GA) induced statistically validated elevation of GRP78 content (1.9 times) only in A431 cells (Figure 2t), but a trend towards the increase in GRP78 production was observed in human cells—immortalized non-tumorigenic keratinocytes (HaCaT) cells (Figure 2s)
We found that plant hormone GA increased the expressional level of mRNA for the ER stress genes (ATF4, CHOP, sXBP1, and GRP78) in cultured human cells of epidermoid origin—immortalized keratinocytes HaCaT and carcinoma A431cells—but in a slightly different manner for ATF4

Summary

Introduction

Plant hormones are biologically active substances of low molecular weight and diverse chemical composition. They are produced by plant cells and regulate many physiological processes, such as stress responses, stimulation or inhibition of plant development, growth, and differentiation [1]. As components of natural origin with specific activity, plant hormones have been appealing objects of investigation in terms of their impact on animal and human cells. It has been demonstrated that certain plant hormones can affect specific cellular functions and even exhibit selective cytotoxicity against tumor cells [4,5,6,7], and molecular modifications of these compounds might substantially enhance these properties [3,8].

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