Effects of Inorganic Arsenic on Prostate Cancer Development

Prostate cancer is one of the leading indications affecting men today, with an estimated 1 in 9 men diagnosed in their lifetime. Significant effort is being put behind understanding the biology of the male prostate and studying the mechanisms that drive tumorigenesis in hopes of finding ways to mitigate cancer progression or to identify potential treatments for this disease.

The male prostate is composed of glandular tissue that is lined with secretory epithelial cells. These epithelial cells are purported to be the cells of origin for prostate cancer. Therefore, prostate epithelial cells are ideal in vitro models to study normal prostate function and disease progression of prostate cancer. A previous blog described the use of Lifeline®’s normal human prostate epithelial cells (HPrEC) to identify new biomarkers to facilitate early detection of prostate cancer. More recently, Xie and Colleagues utilized Lifeline’s HPrEC cultured in ProstaLife Medium to study the link between environmental toxins and prostate cancer risk.

Research Using Lifeline Prostate Epithelial Cells

Chronic exposure to environmental toxins, like inorganic arsenic (iA) can increase the risk of prostate cancer. However, the mechanisms by which iA induces prostate carcinogenesis is unclear. Xie and colleagues sought to determine its effects on normal human prostate stem-progenitor cells (PrSPCs) and elucidate the molecular mechanisms that cause their tumorigenic transformation.

The researchers focused on the effects of iA on two unique properties of stem-progenitor cells: self-renewal (homeostasis) and differentiation. PrSPCs were isolated from Lifeline’s normal HPrECs using 3D spheroid culture (prostaspheres) to study the effects of iA on prostate homeostasis. Perturbations in differentiation capability were evaluated using HPrEC-derived prostate organoids.

At environmentally relevant doses of iA (1μM) PrSPC homeostasis was affected, manifesting in enhanced cellular proliferation and suppression of epithelial differentiation. Microarray analysis of 1μM iAs-treated PrSPCs showed activation of oncogenic pathways including the KEAP1/NRF2 pathway. The correlation of iA-induced tumorigenesis and NRF2 activation was confirmed by NRF2 knockdown assays.

Previous studies show that autophagy, a process by which a cell degrades its own cytoplasmic material via the lysosome, plays a key role in maintaining PrSPC homeostasis, which lead the authors to investigate iAs-induced NRF2 activation in this process. LysoHunt Red, a fluorescent dye that localizes to acidic organelles of living cells, revealed that iAs suppressed lysosome acidification within the PrSPCs, inhibiting autophagy.

The enzyme vacuolar ATPase (V-ATPase) is required for lysosome acidification and VMA5 is essential for its assembly. Knockdown of the VMA5 gene demonstrated that the presence of iA suppressed V-ATPase function and prevented lysosome acidification, causing autophagic flux blockade. This iA-induced blockade results in accumulation of p62, which led to the finding that iA activates NRF2 through the noncanonical p62/NRF2 pathway.

Further testing by the authors suggests that the progenitor cells are the primary targets for iA and more importantly, iA-induced NRF2 activation of progenitor cells is passed down to their progeny cells. While prostate cancer manifests in the epithelial cells, this model suggests that their predecessors, the progenitor cells, are the source of transformative changes that accumulate as a result of homeostatic dysfunction that can make the differentiated epithelial cells susceptible to tumorigenesis.

Taken together, the authors postulate that iA exposure prevents the correct assembly of V-ATPase in PrSPCs inhibiting lysosome acidification, which results in accumulation of p62 and subsequent activation of NRF2, leading to cellular transformation. Importantly, this dysfunction in homeostasis is preserved and transmitted, persisting into later generations of progeny cells predisposing them to a carcinogenic state, increasing one’s risk of prostate cancer. This key role of autophagy may shed light on novel strategies to target its regulation to mitigate adverse effects of iA or as potential therapeutic targets to treat prostate cancer.

Lifeline Male Reproductive & Prostate Cells

For information on Lifeline’s normal male prostate and reproductive cells, click on the links below:

• Normal Human Prostate Epithelial Cells
• Prostate Smooth Muscle Cells
• Human Prostate Fibroblasts
• Normal Human Vas Deferens Fibroblasts
• Human Seminal Vesicle Epithelial Cells

Have you used Lifeline Cell Technology products to study prostate development and prostate cancer? Share your experience and findings with us!