A "light" touch on PI3K to interrogate cancer drug resistance

Tianlu Wang1, Yuepeng Ke1, Yubin Zhou2

  • 1Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.

Cell Chemical Biology
|November 18, 2022
PubMed

Insights

Researchers developed PPAP2, an optogenetic tool to control PI3K signaling in cancer. Enhanced TNFAIP8 translation may cause resistance to DNA-damaging cancer drugs.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Optogenetics

Background:

  • Phosphoinositide 3-kinase (PI3K) signaling is crucial in cancer.
  • Optogenetic tools offer precise control over cellular pathways.
  • Drug resistance remains a significant challenge in cancer therapy.

Purpose of the Study:

  • To develop an improved optogenetic tool for inducing PI3K signaling hyperactivation.
  • To investigate the mechanisms underlying resistance to DNA-damaging agents in cancer cells.

Main Methods:

  • Development and application of the PPAP2 optogenetic tool.
  • Analysis of PI3K signaling pathways.
  • Investigation of protein translation, specifically TNFAIP8.
  • Assessment of cancer cell response to alkylating agents.

Main Results:

  • PPAP2 was successfully developed as an optogenetic tool to photo-induce PI3K signaling hyperactivation.
  • Enhanced translation of tumor necrosis factor alpha-induced protein 8 (TNFAIP8) was observed.
  • This TNFAIP8 upregulation may contribute to resistance against DNA-damaging anti-cancer drugs.

Conclusions:

  • PPAP2 serves as a valuable optogenetic tool for studying PI3K signaling in cancer.
  • Enhanced TNFAIP8 translation is a potential mechanism driving resistance to alkylating agents.
  • Understanding this resistance mechanism could inform future cancer treatment strategies.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.0K