Human Cells Secrete Cancer-killing Protein.

**nkira** · 07-25-2009, 12:16 PM

Human Cells Secrete Cancer-killing Protein

ScienceDaily (July 23, 2009) — Human cells are able to secrete a cancer-killing protein, scientists at the University of Kentucky's Markey Cancer Center have found.

Researchers led by Vivek Rangnekar, UK professor of radiation medicine, have determined that the tumor-suppressor protein Par-4, initially thought to be active only within cells expressing the Par-4 gene, is in fact secreted by most human and rodent cells and can target large numbers of cancer cells by binding to receptors on the cell surface.
This discovery, published today in the leading journal Cell, makes Par-4 a very attractive molecule for future research aimed at developing new cancer treatments.
"It was a pleasant surprise, when we noticed that Par-4 protein is secreted by cells," Rangnekar said. "This new finding means it is not necessary to make genetic modifications, or to employ recombinant viruses, to deliver the Par-4 gene to cancer cells, and it significantly expands the potential applications of Par-4 to selectively kill cancer cells."
Funded by several grants from the National Institutes of Health, Rangnekar's study found that when the Par-4 molecule binds to its receptor GRP78 on the surface of a tumor cell, it triggers a biological process called apoptosis or "cell suicide." Consistent with previous research by Rangnekar's laboratory with intracellular Par-4, the newly discovered secreted Par-4 acts selectively against cancer cells, leaving healthy cells unharmed. Few other molecules are known to exhibit such selectivity.
One molecule, known as TRAIL, also exerts cancer-cell-specific effects. However, Rangnekar's most recent study discovered that apoptosis inducible by TRAIL is dependent upon extracellular Par-4 signaling via cell surface GRP78. Thus, the researchers conclude, Par-4 activates a novel pathway involving cell surface GRP78 receptor for induction of apoptosis. In other words, without Par-4, TRAIL lacks the ability to cause "cell suicide."
Rangnekar first discovered the Par-4 gene in 1993. In 2007, Rangnekar's team introduced the gene into a mouse embryo, creating a cancer-resistant "supermouse" that did not develop tumors. In fact, the mice possessing Par-4 actually live a few months longer than lab mice without the gene, indicating that Par-4 mice have no toxic side effects.
While Par-4 is not necessarily a "magic bullet" — it does not target every type of cancer cell — Rangnekar says it could play a major role in developing new combination treatment modalities for cancer patients. His hope is that the next generation of treatments will be even more effective than conventional treatments available today, with fewer and less severe side effects.
"I look at this research from the standpoint of how it can be developed to benefit the cancer patient, and that's what keeps us focused," Rangnekar said, discussing the potential of Par-4 in 2007. "The pain that cancer patients go through — not just from the disease, but also from the treatment — is excruciating. If you can treat the cancer and not harm the patient, that's a major breakthrough."
Rangnekar holds the Alfred Cohen, M.D., Endowed Chair in Oncology Research at the UK College of Medicine.
Adapted from materials provided by University of Kentucky, via EurekAlert!, a service of AAAS.

Source

'Supermouse' bred to beat cancer.

**StacyCaliman** · 07-25-2009, 12:34 PM

Thanks... I think?

**Gazhole** · 07-25-2009, 03:18 PM

This is really interesting...do the secretions of this par-4 need to be activated in some way? Surely if all human cells secrete this cancer-killing molecule nobody would ever get cancer?

**bandaidwoman** · 07-25-2009, 06:36 PM

Originally Posted by Gazhole

This is really interesting...do the secretions of this par-4 need to be activated in some way? Surely if all human cells secrete this cancer-killing molecule nobody would ever get cancer?

Tumor cell aptosis or killing of tumor cells occurs on regular basis in our bodies , it's when cell proliferation and aptosis goes awry that we get cancer. How some cancer cells escape or outsmart our natural antitumor defenses is the subject of continuing research... (oncogenes etc.) Some cancers already are not susceptible to the par-4 activation pathway as the article stated.(i believe a type of kidney cancer, renal cell carcinoma is one of them)

Another example of great ground breaking medical research sponsered by the NIH, it's good to know your tax dollars are hard at work.

**maniclion** · 07-25-2009, 07:00 PM

Originally Posted by Gaz

This is really interesting...do the secretions of this par-4 need to be activated in some way? Surely if all human cells secrete this cancer-killing molecule nobody would ever get cancer?

when the Par-4 molecule binds to its receptor GRP78 on the surface of a tumor cell, it triggers a biological process called apoptosis or "cell suicide.

Maybe future nano tech can find a way to deliver or lead the PAR-4 to cancerous cells and if the GRP78 isn't present or doesn't respond it can then attach to the cancer cells and mimic the receptor

**KelJu** · 07-25-2009, 08:34 PM

Holy hell, a decent thread worth checking IM for.
Thank you nkira, that was a good read.

**nkira** · 07-25-2009, 10:32 PM

I am not challenging, Peace.

``Par-4, secreted inside the human body by the kidney, lung and prostate, can now be developed so as to inject the protein to treat cancer. Not only primary tumours, but also metastatic tumours that have spread to other tissues should be killed by the Par-4 protein,'' Dr Rangnekar, who spent over 25 years of his life in Matunga, Mumbai, told TOI."

Source

I am not that good at this "gene" business, but since this Par-4 is secreted by human body then there has to be some thing that promotes synthesis of Par-4 or serves as the precursor for the synthesis of Par-4, yes/no?

Originally Posted by bandaidwoman

Tumor cell aptosis or killing of tumor cells occurs on regular basis in our bodies , it's when cell proliferation and aptosis goes awry that we get cancer. How some cancer cells escape or outsmart our natural antitumor defenses is the subject of continuing research... (oncogenes etc.) Some cancers already are not susceptible to the par-4 activation pathway as the article stated.(i believe a type of kidney cancer, renal cell carcinoma is one of them)

Another example of great ground breaking medical research sponsered by the NIH, it's good to know your tax dollars are hard at work.

**nkira** · 07-25-2009, 10:51 PM

Actual trial's on mice (Scientific Report).

Tumour-suppression activity of the proapoptotic regulator Par4

**Gazhole** · 07-26-2009, 05:13 AM

This is great stuff, i like threads that really make me think.

**bandaidwoman** · 07-26-2009, 06:13 AM

Originally Posted by nkira

I am not challenging, Peace.

I'm sorry, I didn't mean to sound too harsh, I was answering Gazhole's question.

I am not that good at this "gene" business, but since this Par-4 is secreted by human body then there has to be some thing that promotes synthesis of Par-4 or serves as the precursor for the synthesis of Par-4, yes/no?

That is what is perplexing, we thought initially that the cells that secreted Par-4 had to have the gene for encoding it but it looks like they don't. So the real but much harder question to answer is how are these cells doing it? ( as you eluded to). I'm sure many other researchers are now looking into it.
But it is exciting to know that maybe we don't have to introduce recombinant viruses to genetically modify cells ( a expensive and laborous process) to achieve our goal of delivering a suicide pill to the cancer cell.

**nkira** · 07-26-2009, 07:39 AM

This is really interesting,

"PAR-3 and PAR-4 can be activated by both thrombin and trypsin"

It's a Google doc, Page 153, Paragraph below Table 11.3.

Source

bandaidwoman, I see that you are Associate Professor of Medicine & Clinical medical researcher, I would really like to know your thoughts on this from practical usage point of view.

**nkira** · 07-26-2009, 07:47 AM

This Pubmed article also mention's,

" PAR1, PAR3, and PAR4 can all be activated by thrombin."

Source

**bandaidwoman** · 07-26-2009, 12:45 PM

The problem with using thrombin is that thrombin activation of platelet aggregation ( sticking together) is a major player in ischemic strokes and cardiovascular events and heart attacks. I'm afraid they will have to find another signaling pathway that is more specific in activating Par 4 and not something that has such broad effects in triggering a pathway that is intrinsically involved in cardiovascular disease. Hate to kill the cancer and kill the patient with a stroke and heart attack.

**nkira** · 07-26-2009, 10:07 PM

Ok, You are referring to clot formation (thrombosis).

Thrombus formation is also a complex process. (Just read about Platelet )

This field is really interesting, Considering the workaholic you are I bet you enjoy your work, yes?

In this field there's always something new happening, everyday there are new different unique cases, I am sure there are some down sides but at least from my point of view this field IS interesting.

**bandaidwoman** · 07-28-2009, 09:27 AM

Originally Posted by nkira

Ok, This field is really interesting, Considering the workaholic you are I bet you enjoy your work, yes?

Yes, it's the best job in the world, could use a little more sleep, there are nights when I work all night in the ICU or ER and still put in 30 hours straight at least once a week but overall, it is a great job. There are ups and downs like any other job. It helps to teach since the med students keep me excited.

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