Prostate cancer : drug that targets a protein called PHLPP2 may prevent the cancer cells from spreading to other organs in the body

0
436

Researchers in New York have found that treating human prostate cancer cells with a drug that targets a protein called PHLPP2 may prevent the cancer cells from spreading to other organs in the body.

The study, which will be published May 15 in the Journal of Cell Biology, reveals that inhibiting PHLPP2 lowered the levels of MYC, an oncogenic protein that causes many different types of cancer that cannot be targeted by conventional drug therapies.

MYC is a powerful oncogene because it drives cell growth and proliferation and enhances cell metabolism and survival.


Postmortem luciferase analysis confirms cancer metastasis to secondary organs. Credit: Trotman lab/CSHL

“It is estimated that 450,000 Americans are diagnosed each year with a cancer that is driven by MYC,” says co-senior author Dawid G. Nowak, who is currently an assistant professor at Weill Cornell Medicine.

One type of cancer associated with elevated MYC levels is metastatic prostate cancer.

According to the American Cancer Society, around one in nine men will be diagnosed with prostate cancer during their lifetime.

The disease is the second leading cause of cancer death among American men and is projected to kill over 30,000 people in 2019.

The vast majority of these deaths are the result of cancers that spread, or metastasize, from the prostate to other organs in the body.

“The five-year survival of metastatic prostate cancer is only 28%, whereas the five-year survival of prostate-confined disease is almost 99%,” explains Lloyd C. Trotman, a professor at Cold Spring Harbor Laboratory and co-senior author of the new study.

The protein PHLPP2 is also elevated in metastatic prostate cancer cells.

PHLPP2 is a phosphatase enzyme that can remove phosphate groups from other proteins, but the role of this protein in prostate cancer was previously unclear.



Anti-PHLPP2 antibody IHC of human kidney. Immunohistochemistry of formalin-fixed, paraffin-embedded tissue after heat-induced antigen retrieval. Antibody dilution 1:50.

Pleckstrin homology domain leucine-rich repeat protein phosphatases, including PHLPP1 and PHLPP2, have been identified as phosphatases with PH domains [5].

Generally, the PHLPP family members are considered as tumor suppressors in several types of cancer due to their ability to block growth factor-induced signaling pathway in cancer cells [67].

PHLPP2 has been identified by our lab to inhibit lung carcinogenesis following B[a]P/B[a]PDE exposure [8].

Moreover, we demonstrate that PHLPP2 is involved in NFκB2-mediated inhibition of BC growth [9].

However, little is known whether PHLPP2 is involved in modulation of the invasion ability of bladder cancer.

p27Kip1 is a negative cell cycle regulatory gene that plays a central role in the transition from late G1 to S phase [10].

Although mutation of the p27 gene is rare in human cancers, decreased p27 protein levels are found in multiple kinds of cancer, including BCs, and are associated with poor prognosis of the BC patient [11,12,13,14,15].

Furthermore, decreased p27 and cyclin E have been associated with the progression of BC from a superficial to invasive phenotype, indicating the involvement of p27 in modulation of BC invasion [16].

Calpains, which are represented by two main ubiquitously expressed isoforms, calpain1 and calpian2, are proteolytic enzymes that belong to a family of the Ca2+-dependent proteases.

Calpains are able to specifically degrade members of protein complexes that are required to regulate and elicit cell responses [1718].

Moreover, calpain1 was identified to interact directly with Hsp90 in human T cells [19].

Autophagy is found to be a lysosome-based degradation mechanism of cytosolic cargos during an adaptation of cells to starvation or other stimulation [2021].

p62/SQSTM1 is a member of the growing list of autophagic receptors characterized by the presence of a LC3-interacting region (LIR), which allows interaction with the autophagic machinery [2223].

Limited reports indicate that p62 liberates Beclin1, thus inducing autophagy [24].

Though autophagy has been widely studied, little is known about its role in BC invasion, and more evidence is needed to fully illustrate the interplay among p62, autophagy and BC invasion.


In the new study, Nowak, Trotman, and colleagues found that metastatic prostate cancer cells require PHLPP2 to survive and proliferate.

They discovered that PHLPP2 helps stabilize MYC by removing a phosphate group that would otherwise trigger MYC’s destruction.

The researchers deleted the Phlpp2 gene in mice and found that doing so prevented prostate cancer cells from metastasizing to other organs.

This is significant because researchers have been unable to develop treatments that directly inhibit MYC, as it does not contain any features that can be easily targeted with a drug.

  • PHLPP2 gene alterations across different cancer types that have at least 10% of cumulative alterations Credit: Trotman lab/CSHL
  • Postmortem luciferase analysis confirms cancer metastasis to secondary organs. Credit: Trotman lab/CSHL
  • PHLPP2 gene alterations across different cancer types that have at least 10% of cumulative alterations Credit: Trotman lab/CSHL
  • Postmortem luciferase analysis confirms cancer metastasis to secondary organs. Credit: Trotman lab/CSHL

Trotman and colleagues then turned to human prostate cancer cells, which they treated with a drug that inhibits PHLPP2. This lowered MYC levels and caused the cells to stop proliferating and die.

PHLPP2 does not appear to perform any essential functions in healthy cells, so researchers suggest the enzyme could be an attractive way to indirectly target MYC in metastatic prostate cancer and possibly other cancers, too.

“Our results suggest that targeted efforts to design pharmacologically relevant PHLPP2 inhibitors could result in very efficient new drugs that suppress MYC-driven cancer,” Trotman says.

More information: Nowak et al., 2019. J. Cell Biol.jcb.rupress.org/cgi/doi/10.1083/jcb.201902048

Journal information: Journal of Cell Biology
Provided by Rockefeller University Press

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.