# CXCL12/CXCR4 regulation of PI4KIIIalpha activity in metastatic prostate tumors

> **NIH NIH R21** · WAYNE STATE UNIVERSITY · 2021 · $179,988

## Abstract

Principal Investigator/Program Director (Last, First, Middle): Chinni, Sreenivasa, R
Castrate resistant prostate cancer (CRPC) is a debilitating disease and currently resistant to available
therapies. Bone metastasis is predominant in these patients and understanding the molecular pathways
driving CRPC progression constitutes a fundamental gap in knowledge. Our previous work focused
on CXCL12/CXCR4 signaling promoting homing of prostate cancer (PC) cells to bone and found that
phosphoinositide signaling (PI4KIII and Sac1) cross talk with CXCL12/CXCR4 in PC cells. The
long-term goal is to understand the biological and molecular mechanisms governing CRPC develop-
ment. The objective of this application is to identify how the CXCR4-PI4KIII axis promotes PC
bone tumor growth by their function in cancer cells. The central hypothesis is that CXCR4-PI4KIII
crosstalk confers PC cell invasion and that CXCR4 induced cellular changes in bone metastasis pro-
mote growth and structural changes in bone via tumor induced bone modification. Guided by novel
preliminary data, this hypothesis will be tested by pursuing by following specific aims: 1) Characterize
interaction between CXCR4 and PI4KIII and impact of interaction in prostate cancer cell invasion,
and 2) Determine the biological and clinical significance of PI4KIII signaling in intraosseous expan-
sion of prostate tumors. The specific aims will be carried out using molecular biology, confocal imag-
ing, in vitro lipid kinase activity, in vivo intra-tibial bone tumor growth assay and gene expression
analysis of human prostate metastatic biopsy specimens. Known function of GPCRs is to cleave
PI(4,5)P2 in cell membrane through phospholipase C activation and thus dependent on high levels of
PI(4,5)P2 in PM for cellular signaling. Our data points to a novel GPCR function in generating PI4P
in plasma membrane through recruitment and activation of PI4KIII We will crucially address the
relevance of CXCR4- PI4KIII in prostate cancer cell invasion and metastatic growth in bone.
Summary

## Key facts

- **NIH application ID:** 10070587
- **Project number:** 5R21CA235541-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** SREENIVASA R CHINNI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $179,988
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070587

## Citation

> US National Institutes of Health, RePORTER application 10070587, CXCL12/CXCR4 regulation of PI4KIIIalpha activity in metastatic prostate tumors (5R21CA235541-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10070587. Licensed CC0.

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