# Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $503,644

## Abstract

SUMMARY
The process by which not only cancer cells but also other components of the tumor microenvironment respond
to nutritionally challenging conditions is not well known. The proposed study will provide a detailed
understanding of the mechanisms whereby the PCa epithelium educates the stroma by downregulating p62,
and how p62-deficient stroma reprograms its metabolism to generate a microenvironment more resistant to
nutrient stress. This application is based on two sets of preliminary data: 1) p62-deficient stromal cells
reprogram their metabolism to mediate stromal resistance to glutamine (Gln) deprivation, and promote the
growth of PCa epithelial cells even under Gln-limiting conditions; 2) stromal p62 is downregulated by lactate
secreted by the PCa epithelium by JunB-mediated repression of the p62-promoter. Based on these data, we
hypothesize that p62 downregulation in the stroma by PCa cells constitutes a tumor strategy for the PCa
epithelium to obtain the metabolic support necessary to proliferate under the Gln-deprived tumor
microenvironment. We will address this fundamental problem in cancer biology in the following Aims: (1)
Define how p62 deficiency reprograms stromal metabolism in Gln-deprived conditions. We hypothesize that
ATF4 upregulation is central to the mechanisms whereby the loss of p62 in stromal cells reprograms glucose
metabolism to compensate for the lack of Gln. To test this hypothesis, we will: (1A) Mechanisms of ATF4
regulation by the p62-PKCλ/ι complex; (1B) Define how p62 deficiency reprograms serine/glycine metabolism
in response to Gln deprivation through PKCλ/ι-ATF4; (1C) Define how p62 deficiency promotes Asn synthesis
in response to Gln deprivation through PKCλ/ι-ATF4; (1D) Define how the p62-PKCλ/ι-ATF4 signaling
cascade regulates pyruvate metabolism; (1E) Determine the functional relevance of p62-dependent stromal
metabolic reprograming in PCa in vivo. (2) Define how p62 is downregulated by PCa in the tumor stroma: To
unravel the mechanisms that regulate p62 repression in this context, we will: (2A) Identify the lactate-
responsive AP-1 site in the p62 promoter; (2B) Characterize the JunB-containing AP-1 complex regulated by
lactate; (2C) Define the role of NRF2 in JunB-mediated p62 repression; (2D) Define the biological relevance of
the identified transcription factors and signaling pathways that induce p62-downregulation. This innovative
proposal will fill a key gap in the cancer metabolism field by defining the relationship between metabolic
rewiring and signaling in the tumor stroma and its impact on PCa progression. The impact of these findings will
instruct new therapeutic strategies aimed at manipulating the metabolism of the stroma.

## Key facts

- **NIH application ID:** 9970425
- **Project number:** 5R01CA218254-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Maria Teresa Diaz Meco Conde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,644
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970425

## Citation

> US National Institutes of Health, RePORTER application 9970425, Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer (5R01CA218254-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970425. Licensed CC0.

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