protein that determines effectiveness (or ineffectiveness) of taxanes identified

[Lani]

Protein Identified That Regulates Effectiveness of Taxol Chemotherapy in Breast Cancer [Georgetown University Medical Center]
Washington, DC — Researchers at Georgetown University Medical Center have taken a step towards understanding how and why a widely used chemotherapy drug works in patients with breast cancer.

In laboratory studies, the researchers isolated a protein, caveolin-1, showing that in breast cancer cells this protein can enhance cell death in response to the use of Taxol, one of two taxane chemotherapy drugs used to treat advanced breast and ovarian cancer. But in order to work, they found the protein needs to be "switched on," or phosphorylated. The results were reported in the current (February 23) issue of the Journal of Biological Chemistry.

Their finding suggests it may eventually be possible to test individual breast cancer patients for the status of such molecular markers as caveolin-1 in their tumors to determine the efficacy-to-toxicity ratio for Taxol, said the study's first author, postdoctoral fellow Ayesha Shajahan, Ph.D., of Lombardi Comprehensive Cancer Center at Georgetown. "Because breast tumors are not all the same, it is important to know the cancer's molecular makeup in order to increase the efficiency, and lower the toxicity, of chemotherapy drugs, and this work takes us some steps forward in this goal," she said. "It also offers insights into why some breast cancer cells can become resistant to therapeutic drugs."

Additionally, the study identifies caveolin-1 as a new molecular target for increasing the efficacy of taxanes, according to the study's lead investigator, Robert Clarke, Ph.D., D.Sc., a Professor of Oncology and Physiology & Biophysics.

"This is important because the taxanes are active drugs in breast cancer, so now that we know caveolin-1 is a new mechanism to explain how these drugs kill breast cancer cells, we can potentially take advantage of that fact to improve these agents."

The taxanes are Taxol (also known as paclitaxel) and Taxotere (docetaxel). Taxol was originally derived from the Pacific yew tree, and Taxotere is a semi-synthetic version of Taxol with slight chemical changes. These drugs stabilize a cell's "microtubules," the road-like protein structures that send chemical signals to all parts of the cell, and which must be flexible if a cell is to divide. Taxanes lock these structures into place, not allowing them to change when the cell begins to divide — which is necessary for tumor growth.

Research has also indicated that the drugs induce programmed cell death (apoptosis) in cancer cells by inactivating an "apoptosis stopping protein" called BCL2, thus stopping it from inhibiting cell death. Caveolin-1 is a protein that is found in most cells under normal conditions and it is involved in an array of cellular events that ranges from vesicle trafficking to cell migration. It is, therefore, as a key regulator of multiple events within the cell. In cancer, the expression level of caveolin-1 can vary depending on cell type.

However, the precise role of caveolin-1 in cancer has been controversial: whether it acts as a suppressor or facilitator of tumor formation depends on the cell type. In human breast cancer, caveolin-1 has been known to act as a tumor suppressor since caveolin-1 expression is down-regulated during the primary stages of breast cancer. More recent studies indicate that that caveolin-1 expression is increased in more aggressive types of breast cancer. Under the mentorship of Clarke, Shajahan sought to determine factors that regulate expression and function of caveolin-1 in the breast. In this study, the researchers show that in their breast cancer cell model that phosphorylated caveolin-1 increased cell death by activating other key regulators vital to both breast cancer progression and cell death, including BCL2, the same protein that Taxol works on; p21, which controls cell cycle progression; and the tumor suppressor p53. If caveolin-1 isn't phosphorylated, breast cancer cells appear to be resistant to Taxol treatment, the researchers conclude.

"Thus, this study opens an area of investigation in our lab that will concentrate on understanding how this multi-tasking protein can serve as a marker for chemotherapeutic drug efficacy," Shajahan said.

The study was supported by grants from the National Institute of Health, and the Department of Defense to Clarke and a postdoctoral fellowship award from Susan G. Komen Breast Cancer Foundation to Shajahan. The other co-authors for this study were Aifen Wang, M.Sc., Markus Decker, B.Sc., and . Minetta C. Liu, M.D. from Georgetown University Medical Center, and Richard D. Minshall, Ph.D. from the University of Illinois at Chicago.


ABSTRACT: Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity [Journal of Biological Chemistry]
Caveolin-1 (CAV1), a highly conserved membrane-associated protein, is a putative regulator of cellular transformation. CAV1 is localized in the plasmalemma, secretory vesicles, Golgi, mitochondria, and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton. Taxanes such as paclitaxel (Taxol) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G2/M phase. Src phosphorylation of Tyr-14 on CAV1 regulates its cellular localization and function. We report that phosphorylation of CAV1 on Tyr-14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells. Befitting its role as a multitasking molecule, we show that CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules BCL2, p53, and p21. We demonstrate that phosphorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non-phosphorylated CAV1. Furthermore, expression of p21, which correlates with taxane sensitivity, is regulated by CAV1 phosphorylation in a p53-dependent manner. Collectively, our findings underscore the importance of CAV1 phosphorylation in apoptosis and suggest that events that negate CAV1 tyrosine phosphorylation may contribute to anti-microtubule drug resistance.