cancer · molecular biology · molecular pharmacology

Jalur transduksi sinyal Wnt dalam kanker

Apakah jalur transduksi sinyal Wnt?

Jalur transduksi sinyal Wnt adalah jalur molekuler yang berperan penting dalam pembentukan organ (organogenesis) saat perkembangan embryo. Jalur ini mengatur berbagai aspek dalam sel, antara lain penentuan jenis sel, pembelahan sel, migrasi sel, polaritas sel, pembentukan pola neuron, dan proses seluler lainnya.

Wnt adalah suatu glikoprotein, yang jika teraktivasi, akan berikatan dengan reseptor Frizzled (Fz, suatu protein transmembran). Dengan kata lain, Wnt adalah ligan dari Fz. Terdapat beberapa jenis jalur transduksi Wnt. Terkadang diperlukan protein lain sebagai ko-reseptor Fz untuk menangkap Wnt, antara lain adalah low-density-lipoprotein-related protein5/6 (LRP5/6).

 

Jalur canonical vs non-canonical

Hingga saat ini, peneliti sudah berhasil mengkarakterisasi tiga jalur transduksi sinyal Wnt, yaitu: 1) jalur canonical; 2) jalur non-canonical PCP; 3) jalur non-canonical Ca2+. Perbedaan antara kedua jalur tersebut adalah keterlibatan protein β-catenin. Jalur canonical melibatkan β-catenin, sementara jalur non-canonical tidak melibatkan β-catenin.

1) Jalur canonical

Jalur canonical berkaitan erat dengan akumulasi protein β-catenin dan translokasi β-catenin dari sitoplasma ke nukleus, yang pada akhirnya mengaktifkan ekspresi berbagai gen yang terlibat dalam proliferasi sel, migrasi sel, dll.

Saat tidak terjadi aktivasi jalur transduksi Wnt (tidak ada interaksi antara ligan Wnt dan reseptor Fz/LRP5/6), β-catenin berada dalam suatu kompleks protein yang disebut sebagai destruction complex. Kompleks protein ini terdiri dari protein DVL, axin, CKI, GSK3, APC, dan β-TrCP. Kompleks protein tersebut akan memfosforilasi β-catenin, dan protein β-TrCP akan mengubiquitinasi β-catenin, yang pada akhirnya menyebabkan degradasi β-catenin melalui jalur proteasomal. Akibatnya, level β-catenin dalam sel tetap terjaga rendah saat tidak ada sinyal Wnt.

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Ketika jalur Wnt teraktivasi (Wnt berinteraksi dengan reseptor Fz/LRP5/6), destruction complex akan tertarik untuk berinteraksi dengan reseptor Fz. LRP5/6 juga memfosforilasi destruction complex, terutama axin, dan menyebabkan turunnya level axin di dalam sel. Protein DVL juga teraktivasi dan menghambat aktivitas protein GSK3 dan destruction complex secara keseluruhan. Akibatnya, β-catenin terlepas dari destruction complex dan levelnya meningkat di dalam sel. Selanjutnya, β-catenin bertranslokasi ke dalam nukleus dan berinteraksi dengan faktor transkripsi TCF/LEF (T-cell factor/lymphoid enhancing factor) untuk mengaktifkan transkripsi berbagai gen. Contoh gen yang diaktifkan transkripsinya adalah Siamois dan Twin (terlibat dalam organogenesis), serta Myc dan CyclinD1 (yang terlibat dalam proliferasi sel dan kanker).

2) Jalur non-canonical PCP

Jalur non-canonical PCP (planar cell polarity) tidak melibatkan β-catenin dan ko-reseptor LRP5/6. Namun, jalur ini memiliki beberapa kandidat ko-reseptor, seperti NRH1, Ryk, PTK7, dan ROR2. Terdapat 3 cabang dari jalur non-canonical PCP.

a. Sinyal dari kompleks Wnt, reseptor Fz, dan ko-reseptor kemudian mengaktivasi DVL. DVL kemudian menggunakan membentuk kompleks dengan Dishevelled-associated activator of morphogenesis 1 (DAAM1), yang kemudian mengaktifkan Rho. Rho kemudian mengaktifkan Rho-associated kinase (ROCK), yang kemudian akan memodifikasi sitoskeleton aktin.

b. DVL mengaktivasi Rac (dan tidak berkaitan dengan DAAM1). Rac kemudian mengaktivasi JNK dan mengaktifkan jalur yang memodifikasi sitoskeleton aktin.

c. DVL dan DAAM1 menginduksi interaksi antara profilin dengan aktin, yang kemudian menyebabkan restrukturisasi sitoskeleton dan gastrulasi (saat embryogenesis).

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3) Jalur non-canonical Ca2+

Pada jalur non-canonical Ca2+, Wnt berikatan dengan reseptor Fz, yang kemudian mengaktivasi DVL dan protein G trimerik. Ko-stimulasi DVL dan protein G ini kemudian mengaktivasi PDE atau PLC. Jika PLC teraktivasi, komponen membran plasma PIP2 akan terpotong menjadi DAG dan IP3. IP3 kemudian dapat berikatan dengan reseptornya di retikulum endoplasma (RE) dan menyebabkan lepasnya kalsium dari RE. Kenaikan kadar DAG dan kalsium intracellular mengaktivasi PKC, yang kemudian mengaktivasi Cdc42, dan menyebabkan terjadinya pemisahan jaringan dalam organogenesis.

Kalsium juga mengaktifkan protein calcineurin, yang kemudian mendefosforilasi protein sitoplasmik nuclear factor associated with T cells (NFAT). Selanjutnya, NFAT aktif dan menginduksi ekspresi gen-gen yang terlibat dalam perkembangan neuron, sel otot jantung dan rangka, serta berbagai gen pro-inflamasi di limfosit.

Kalsium juga dapat mengaktivasi calcium/calmodulin-dependent kinase II (CamKII). CamKII kemudian mengaktifkan TGF-β-activated kinase (TAK1) dan Nemo-like kinase (NLK), yang selanjutnya dapat menginhibisi jalur transduksi sinyal β-catenin/TCF.

 

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Jalur transduksi sinyal Wnt pada sel normal vs sel kanker

Pada sel normal, level Wnt diregulasi dengan ketat sehingga jalur transduksi sinyal Wnt hanya aktif ketika diperlukan dalam pembelahan dan perkembangan sel atau organ. Regulasi Wnt antara lain melalui:

a) Palmitolasi protein Wnt. Protein Wnt mendapat gugus tambahan asam palmitat, yang dimediasi oleh protein porcupine. 

b) Di matriks ekstra seluler, Wnt distabilisasi oleh proteoglikan Dally dan glipikan 3 sehingga ukuran Wnt menjadi lebih besar. Akibatnya, Wnt sulit untuk berdifusi dan melakukan fungsinya sebagai molekul penghantar sinyal.

c) Terdapat berbagai jenis molekul antagonis Wnt yang menghalangi interaksi Wnt dengan reseptor Fz dan/atau ko-reseptor LRP5/6. Molekul-molekul tersebut antara lain protein Dickkopf (Dkk), Wnt-inhibitor protein (WIF),soluble Frizzled-related proteins (SFRP), Cerebrus, Frzb, dan Wnt inhibitor Wise.

Pada sel kanker, jalurWnt (dan β-catenin) telah diketahui memiliki peran besar dalam perkembangan berbagai jenis kanker. Mutasi protein APC (yang termasuk dalam destruction complex β-catenin) dan hilangnya fungsi protein tersebut, diketahui berkaitan erat dengan perkembangan kanker kolon. Lebih lanjut, aktivasi jalur canonical Wnt juga terdapat pada sebagian besar subtipe leukemia.

Jalur Wnt dan β-catenin juga berperan pada 50% kasus kanker payudara dan berkorelasi dengan penurunan survival pasien. Jalur canonical Wnt berperan besar pada kasus kanker payudara bertipe triple negative (negatif reseptor estrogen, progesteron, dan HER2).

 

Obat anti-kanker dengan target Wnt

Berikut adalah obat-obat antikanker yang dikembangkan dengan target jalur sinyal transduksi Wnt (Zhan et al., 2017).

Screen Shot 2018-10-30 at 07.09.09Screen Shot 2018-10-30 at 07.09.19

 

 

Referensi:

De, A., 2011. Wnt/Ca2+ signaling pathway: a brief overview. Acta biochimica et biophysica Sinica43(10), pp.745-756.

Komiya, Y. and Habas, R., 2008. Wnt signal transduction pathways. Organogenesis4(2), pp.68-75.

Zhan, T., Rindtorff, N. and Boutros, M., 2017. Wnt signaling in cancer. Oncogene36(11), p.1461.

 

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books

Sapiens: A Brief History of Humankind [Book Review]

23692271This book has sat on my bookshelf for about 2 years. Bought when I was in Japan, I blame my ‘research busyness’ not to finish this book. Two years later, I regret that I didn’t finish this earlier. This book is GREAT!

Harari tells us how us, Homo sapiens, end up being the ‘king’ of the world. Apart from my religious perspective, I enjoy his arguments and data presented in this book. He divides the advancement of Sapiens in several revolutions: cognitive, agriculture, scientific, industrial, and ‘permanent’ revolutions.

For me, the scientific and ‘permanent’ revolutions are the best parts of this book. Harari explicates the close relationship between science, capital, and power; which is quite mindblowing for me. Another interesting analysis from him is on how the European ‘dominate’ our world today. He argues that this is because of European’s curiosity on 15-18 centuries that they traveled and explored (and later conquered) other continents. Had China, or Ottoman, or India ‘open’ their eyes and ignorance of the world, they would be the one who dominates the world today. It is interesting for me to know that in 18-century, Asian empires dominated the world economy. In the last part of his book, Harari argues that permanent revolution has changed the way we see family, community, and humankind. State and market are modern people’s parents. And, what is human? What does it mean being a human? With all rapid advancement in technology, it would be more complex to define our humanity in the future.

Here are some interesting notes I take from this book:

  • Biology shapes our history. Harari writes: “Biology sets the basic parameters for the behavior and capacities of Homo sapiens. History takes place within the bounds of this biological arena.”
  • The agricultural revolution was a trap. After the agricultural revolution, there was no chance of human ‘live peacefully’ with nature. Human have mastered our world by sacrificing other organisms (plants, animals)
  • An overview history of money and credit, how credit transforms our society, for worse and better.
  • The characteristics of modern science: (i) the willingness to admit ignorance, (ii) the centrality of observation and mathematics, (iii) the acquisition of new powers.
  • Surviving large wild animals are <10% in today’s world (in mass)!

Finally, this piece is a really worthy food for thought for anyone!

books · review

Letters to a Young Muslim [Book Review]

9781509842629

This is an interesting book written by the former ambassador of UEA to Russia, Omar Saif Ghobash, as collection of letters to his son. Ghobash himself owns a strong background story to invite his son (and other young muslims) to reflect how we should practice Islamic value in this modern world. Ghobash’s father was shooted by another muslim when Ghobash was a child. Furthermore, Ghobash’s mother is a Russian, which introduce him as well to culture other than only arabic muslim.

In most parts of his book, he suggests us to think any Islamic rule and value not only in ‘black vs white’ sides. There’re a lot of aspects on this life, especially in this modern day, and a lot of those aspects lays on grey areas. There’re several arguments and narrations from Ghobash that trigger me to think more about myself as a Muslim, such as:

  • There was no reason to hate anyone. There is no reason to react to the world around you with hatred. You have to understand that someone has made the choice for you when they say you have to hate. The choice is yours and the only way you can make the world a better place is by doing the opposite of hating. It is by loving.” (page 3). He writes these sentences to counter the hatred idealism and action by some of the so-called radical muslim.
  • “What is the essence of Islam? What is it that distinguishes Islam? What is it that makes you a Muslim or something else?” (page 29)
  • Islamic interpretations coming out of the Arabian peninsula are dry and relatively harsh, a reflection of perhaps of the desert environment. Life in the desert was tough and literally a place of black and white.” (page 39). This passage explain a bit why Islam that can be found in Indonesia is on the more moderate side, just my two cents.
  • “What I am saying to you is that you need to make sure that you understand that those with plausible authority (i.e. clergy) are also human beings like you and me. They are human beiings, who can and will be distracted by the traditional human temptations of power, money, and sex.” (page 71). I found this is ridiculous, but to certain extent is exactly a reality.
  • “Rather than thinking in black and white, we should think with all the colors of the rainbow (muslim diversity) and see Islam as a moreally ad ethically rich faith. The blac-an-white approach is one that sets Muslims in conflict with one another neddlessly and robs us all of our humanity.” (page 76)
  • “It is not enough to chant in public that Islam is not violent or radical or angry – that Islam is a religion of peace. We need to take responsibility for the Islam of peace. We need to demonstrate how it is expressed in our lives and the lives of those in our community.” (page 103)
  • Being an outsider is humbling. It makes you realize the humanity of all outsiders. It is often the outsider who has the most interesting view of what life is and can become.” (page 110)
  • “If you want to be a true to your Muslim heritage, then you need to explore its history properly.” (page 147). Furthermore, Ghobash pushes us to find a role model in Islam, aside from ‘warrior or jihadist’ role models. Why don’t we make Avicenna or Al-Khawarizmi as our role models, with their achievements in science and medicine?

Honestly, I enjoy this kind of book and I like the way Ghobash writes this book. His writing flows smoothly, especially as he writes this book as a series of personal letters. He asks the readers to think, instead of pushes his arguments. However, I feel like I need other complementary books about Islamic value in our modern life. Please kindly tell me you have any recommendation 🙂

books · idea

Konmari and my husband (and a bit of book review)

“Japan has the highest level of civilization on our planet!”

That was my friend’s joke on how clean every part of Japan: street, river, (most of) public bathrooms, public transportations, train and bus stations, schools, you name it! Several days ago, Japanese went viral again with their immaculacy. Japan football’s supporter collected their own trash in the football stadion after Japan beat Colombia in the world cup. They even brought large trash bags on their own! Japanese have never failed me with their respectful attitude toward cleanliness. Hence, I’m not surprised that there’s even a cleaning and tidying “guru” from Japan.

Konmari is such a “hip” method of tidying and organizing home. Introduced by Marie Kondo of Japan, this method went viral in instagram or other social media (well, at least in my accounts). We can find lots of Kondo’s organizing principals on youtube, pinterest, or other blogs. Here is a short review video about Konmari method by Marie Kondo (with a nice Japanese-English interpreter). And here is her book: the life-changing magic of tidying up.

Image result for marie kondo book

Basically, there are 3 principals of Konmari:

  • Tidy in one shot, as quickly and completely as possible
  • Sort things by category, not location
  • Choose things to keep by asking ourselves: “Does it spark joy?”

Here is a great checklist on how to tidying using Konmari, step by step.

And, here are several interesting notes I take from this book.

  • To truly cherish the things that are important to you, you must first discard those that have outlived their purpose. (page 61)
  • The point in deciding specific places to keep things is to designate a spot for every thing. (page 131)
  • Storage methods should be as simple as possible. (page 137)
  • Clutter has only 2 possible causes: too much effort is required to put things away or it’s unclear where things belong. (page 142)
  • Piling things is the worst organizing method. The things in the pile virtually disappear because we forget that they even exist. Hence, store things vertically. (page 145)
  • When we really delve into the reasons for why we can’t let something go, there are only 2: an attachment to the past or a fear for the future. (page 181)

Ok. So then, what’s the relation of Konmari with my husband?

The more I read this book, the more I found that my husband has implemented this Konmari in his life before knowing anything about this method. Apparently, my husband is a long-lost sibling of Marie Kondo in term of organizing and tidying! He has special areas for each of his stuff. He always thinks twice before buying something: “can I use this in long-term?”. He unpacks his bag every evening after he comes home. He takes pity on his stuff and becomes sad when any of his worn out. Those traits are exactly what Kondo’s written in her book!

While for me, organizing and tidying home are my worst housewifery skill. Well, apparently, I have my personal tidying guru :))

 

cancer · course notes

Ringkasan : Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

Fungsi Farmakologi dan Toksikologi

  • Pgp adalah protein membran plasma yang dapat menyebabkan multidrug resistance (MDR) melalui pengeluaran senyawa-senyawa xenobiotik dari dalam sel –> menyebabkan resistensi pada beberapa kanker
  • Pgp menghambat uptake seluler obat pada otak, plasenta, testis dan menghambat transport obat dari lumen intestinal ke sel epitel.
  • Pgp memediasi ekskresi obat keluar hepatosis menuju canaliculi empedu dan keluar ginjal menuju urin
  • Pemberian obat yang merupakan substrat dan senyawa inhibitor Pgp secara bersamaan –> memodifikasi farmakokinetik obat dengan meningkatkan bioavailability dan uptake seluler –> menyebabkan ADR dan toksisitas
  • Pemberian obat yang merupakan substrat dan senyawa inducer Pgp secara bersamaan –> penurunan level obat di plasma –> subterapeutik
  • Lokalisasi Pgp di plasenta berperan penting dalam melindungi janin dari paparan senyawa berbahaya –> inhibisi Pgp pada ibu hamil harus diperhatikan karena dapat menyebabkan toksisitas pada ibu hamil

Continue reading “Ringkasan : Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)”