Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells

Shilpa Katta; Arun Srivastava; Rajesh L Thangapazham; Inger L Rosner; Jennifer Cullen; Hua Li; Shashwat Sharad

doi:10.3390/ijms20194891

Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells

Int J Mol Sci. 2019 Oct 2;20(19):4891. doi: 10.3390/ijms20194891.

Authors

Shilpa Katta^{1

2}, Arun Srivastava³, Rajesh L Thangapazham^{4

5}, Inger L Rosner^{6

7}, Jennifer Cullen^{8

9}, Hua Li^{10

11}, Shashwat Sharad^{12

13}

Affiliations

¹ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. shilpa.katta@nih.gov.
² Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. shilpa.katta@nih.gov.
³ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. aruns1207@gmail.com.
⁴ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. rajeshlt@gmail.com.
⁵ Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. rajeshlt@gmail.com.
⁶ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. inger.l.rosner.mil@mail.mil.
⁷ Department of Urology, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, USA. inger.l.rosner.mil@mail.mil.
⁸ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. jcullen@cpdr.org.
⁹ Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. jcullen@cpdr.org.
¹⁰ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. hli@cpdr.org.
¹¹ Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. hli@cpdr.org.
¹² Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. ssharad@cpdr.org.
¹³ Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr., Suite 300, Bethesda, MD 20817, USA. ssharad@cpdr.org.

Abstract

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-β), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-β signaling, including the androgen/TGF-β inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.

Keywords: AR; MYC; TGF-β; chemotherapy; curcumin; metastasis; prostate cancer; signaling pathways.

MeSH terms

Androgens / metabolism
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Movement
Cell Proliferation / drug effects
Computational Biology / methods
Curcumin / pharmacology*
Gene Expression Profiling
Gene Expression Regulation / drug effects*
Gene Ontology
Hormones / metabolism*
Humans
Male
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Proto-Oncogene Mas
Signal Transduction / drug effects

Substances

Androgens
Antineoplastic Agents
Hormones
MAS1 protein, human
Proto-Oncogene Mas
Curcumin

Grants and funding

HU001-004-c-1502 to DGM/Center for Prostate Disease Research Program, Uniformed Services University for the Health Sciences